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  • 1.
    Srivastava, Karnica
    et al.
    Physics Department, University of Lucknow, Lucknow, India.
    Shukla, Anuradha
    Physics Department, University of Lucknow, Lucknow, India.
    Karthick, T.
    Physics Department, University of Lucknow, Lucknow, India;Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Prague, Czech Republic.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Tandon, Poonam
    Physics Department, University of Lucknow, Lucknow, India.
    Sinha, Kirti
    Physics Department, University of Lucknow, Lucknow, India.
    Shimpi, Manishkumar R.
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Kemiteknik.
    Molecular structure, spectroscopic signature and reactivity analyses of paracetamol hydrochloride monohydrate salt using density functional theory calculations2019Ingår i: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 21, nr 5, s. 857-865Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to understand the role of the intermolecular hydrogen bond interactions present in paracetamol hydrochloride monohydrated salt. Paracetamol hydrochloride monohydrate salt (PRA-HCl) and paracetamol (form I) were investigated via vibrational (FT-IR and FT-Raman) spectroscopy and density functional theory (DFT) to gain insight into the hydrogen bond patterns present in these crystalline materials. Two different density functionals, wB97X-D and M062X, were used for the comparison of the results. The geometrical parameters of PRA-HCl and form I obtained using these functional were compared with the crystallographic data, which proved the existence of intra-molecular and intermolecular hydrogen bonds. The C10O2 group of form I forms an intramolecular hydrogen bond, while the O1–H18 group of PRA-HCl forms an intermolecular hydrogen bond with a chloride ion (Cl), resulting in the elongation of the bond length and shift to a lower wavenumber for the O1–H18 group. To examine the potency of hydrogen bonding, quantum theory of atoms in molecules (QTAIM) calculations were performed and the results suggested that O1–H18⋯Cl22 is a strong intermolecular hydrogen bond. The chemical reactivity parameters reveal that the PRA-HCl and PRA-OXA cocrystals are more reactive and softer (low HOMO–LUMO energy gap) in comparison to paracetamol (form I).

  • 2.
    Hyun, Sang-Min
    et al.
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Joon Lee, Benjamin
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Abuzar, Sharif Md
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Lee, Soohun
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Joo, Yechan
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Hong, Seung-Hyeon
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Kang, Han
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Kwon, Kyung-Ae
    Dae Hwa pharmaceutical Co., Ltd., 2145 Nambusunhwan-ro, Seocho-gu, Seoul, Republic of Korea.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Hwang, Sung-Joo
    College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea. Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, Republic of Korea.
    Preparation, characterization, and evaluation of celecoxib eutectic mixtures with adipic acid/saccharin for improvement of wettability and dissolution rate2019Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 554, s. 61-71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Celecoxib (CEL) is a selective cyclooxygenase-2 (COX-2) inhibitor therapeutically indicated for the treatment of rheumatoid arthritis, osteoarthritis, acute pain, and inflammation. However, its poor solubility and dissolution rate significantly hinders its broader application. In this study, eutectic mixtures, as binary pharmaceutical compositions of CEL with adipic acid (ADI) and saccharin (SAC), were identified through a phase diagram and Tammann’s triangle intended to improve the wettability and dissolution rate of poorly water-soluble CEL. The contact angles at 0s in the liquid-solid interface were approximately θs (theta) 79.7° ± 0.50° and 86.65° ± 0.45° for CEL-ADI and CEL-SAC, respectively, which were much lower than the value obtained for CEL (92.05° ± 0.75° θ). Moreover, a comparison of the disk intrinsic dissolution rate and powder dissolution properties demonstrated that eutectic mixtures significantly increased the dissolution rate compared with CEL and physical mixtures. A general relationship was elucidated and indicated that the dissolution rate was increased as the contact angle decreased (correlation coefficient, r = 0.9966 ± 0.0031). Therefore, CEL-ADI and CEL-SAC eutectics may offer a novel formulation strategy to enhance the solubility and oral bioavailability of CEL.

  • 3.
    AlHayali, Amani
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap. College of Pharmacy, University of Mosul, Mosul, Iraq.
    Vuddanda, Parameswara Rao
    Research Centre for Topical Drug Delivery and Toxicology, Department of Clinical and Pharmaceutical Sciences, School of Life and Medical Sciences, University of Hertfordshire, UK.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Silodosin oral films: Development, physico-mechanical properties and in vitro dissolution studies in simulated saliva2019Ingår i: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, artikel-id 101122Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sublingual film dosage forms for drugs used for fast symptomatic treatment have promise because they allow a rapid onset of action. The aim of this study was to prepare films of silodosin intended for sublingual administration for the symptomatic treatment of benign prostatic hyperplasia in men. Hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were used as film-forming polymers. The effects of the polymers and the surfactant tocopherol polyethylene glycol succinate (TPGS) on the physico-mechanical properties and dissolution behavior of the films in simulated saliva were investigated. The eight silodosin oral films developed (F1–F8) contained 8 mg silodosin per 6 cm2 film and HPMC or HPMC-AS in drug:polymer ratios of 1:5 or 1:3, while four also contained TPGS (0.5% w/w). The films were characterized using DSC, TGA, SEM, and PXRD and the mechanical properties were investigated by measuring tensile strength, elongation at break and Young's modulus. The mechanical properties of the films were dependent on the ratio of polymer used. The in vitro dissolution and drug release studies indicated that HPMC-AS films disintegrated more quickly than HPMC films. Silodosin was shown to be dispersed within the polymers. Despite silodosin being submicronized in the HPMC films, the dissolution and drug release rate (time for 80% release) from HPMC films was significantly faster than from HPMC-AS films. TPGS increased the drug release rate to a greater extent with HPMC than with HPMC-AS. The degree of saturation of formulation F4 was >1, which shows potential for improving oral absorption of silodosin.

  • 4.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Conference proceedings of the 4th Masterclass Psychiatry: Transcultural Psychiatry–Diagnostics and Treatment, Luleå, Sweden, 22–23 February 2018 (Region Norrbotten in collaboration with the Maudsley Hospital and Tavistock Clinic London)2018Proceedings (redaktörskap) (Refereegranskat)
  • 5.
    Ariane, Mostapha
    et al.
    School of Chemical Engineering, University of Birmingham.
    Kassinos, Stavros
    Department of Mechanical and Manufacturing Engineering, University of Cyprus.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Alexiadis, Alessio
    School of Chemical Engineering, University of Birmingham.
    Discrete multi-physics simulations of diffusive and convective mass transfer in boundary layers containing motile cilia in lungs2018Ingår i: Computers in Biology and Medicine, ISSN 0010-4825, E-ISSN 1879-0534, Vol. 95, s. 34-42Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this paper, the mass transfer coefficient (permeability) of boundary layers containing motile cilia is investigated by means of discrete multi-physics. The idea is to understand the main mechanisms of mass transport occurring in a ciliated-layer; one specific application being inhaled drugs in the respiratory epithelium. The effect of drug diffusivity, cilia beat frequency and cilia flexibility is studied. Our results show the existence of three mass transfer regimes. A low frequency regime, which we called shielding regime, where the presence of the cilia hinders mass transport; an intermediate frequency regime, which we have called diffusive regime, where diffusion is the controlling mechanism; and a high frequency regime, which we have called convective regime, where the degree of bending of the cilia seems to be the most important factor controlling mass transfer in the ciliated-layer. Since the flexibility of the cilia and the frequency of the beat changes with age and health conditions, the knowledge of these three regimes allows prediction of how mass transfer varies with these factors.

  • 6.
    Velaga, Sitaram
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Djuris, Jelena
    Department of Pharmaceutical Technology and Cosmetology, University of Belgrade-Faculty of Pharmacy.
    Cvijic, Sandra
    Department of Pharmaceutical Technology and Cosmetology, University of Belgrade-Faculty of Pharmacy.
    Rozou, Stavroula
    Elpen Pharmaceutical Co..
    Russo, Paola
    Department of Pharmacy, University of Salerno.
    Colombo, Gaia
    Department of Life Sciences and Biotechnology, University of Ferrara.
    Rossi, Alessandra
    Food and Drug Department, University of Parma.
    Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products2018Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 113, s. 18-28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In vitro dissolution testing is routinely used in the development of pharmaceutical products. Whilst the dissolution testing methods are well established and standardized for oral dosage forms, i.e. tablets and capsules, there are no pharmacopoeia methods or regulatory requirements for testing the dissolution of orally inhaled powders. Despite this, a wide variety of dissolution testing methods for orally inhaled powders has been developed and their bio-relevance has been evaluated.

    The review provides an overview of the in vitro dissolution methodologies for dry inhalation products, with particular emphasis on dry powder inhaler, where the dissolution behavior of the respirable particles can have a role on duration and absorption of the drug. Dissolution mechanisms of respirable particles as well as kinetic models have been presented. A more recent bio-relevant dissolution set-ups and media for studying inhalation biopharmaceutics were also reviewed. In addition, factors affecting interplay between dissolution and absorption of deposited particles in the context of biopharmaceutical considerations of inhalation products were examined.

  • 7.
    Velaga, Sitaram
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Nikjoo, Dariush
    Luleå tekniska universitet, Institutionen för teknikvetenskap och matematik, Materialvetenskap.
    Rao Vuddanda, Parameswara
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap. Department of Pharmaceutics, UCL School of Pharmacy, University College London.
    Experimental Studies and Modeling of the Drying Kinetics of Multicomponent Polymer Films2018Ingår i: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 19, nr 1, s. 425-435Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The process of drying thin polymer films is an important operation that influences the film structure and solid state, and the stability of the product. The purpose of this work was to study and model the drying kinetics of multicomponent films based on two polymers: hydroxypropyl methylcellulose (HPMC, amorphous) and polyvinyl alcohol (PVA, semicrystalline). The isothermal drying kinetics of the films at different temperatures (40, 60, and 80°C) were studied using thermo-gravimetric analysis (TGA) and convection oven methods. Solid-state characterization tools used in the study included polarization and hot-stage microscopy, scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). The drying kinetics of HPMC and PVA films in the TGA apparatus and convection oven were comparable. The three-parameter (Wmax, τ, n) Hill equation successfully modeled the experimental drying kinetics. The time factor τ in the Hill equation nicely explained two drying phases in the films. Solid-state phase changes occurring in the films during dehydration had a bearing on the drying kinetics and mechanisms. TGA can be used as a simple tool to determine the end points in drying processes using ovens or tunnels. The three-parameter Hill equation explained the drying kinetics and diffusion mechanisms of the solvent through the polymer films for the first time. This study advances our understanding of film drying, in particular for pharmaceutically relevant thin films.

  • 8.
    AlHayali, Amani
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Selo, Mohammed Ali
    School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College, Dublin. Faculty of Pharmacy, University of Kufa, Al-Najaf, Iraq.
    Ehrhardt, Carsten
    School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College, Dublin.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Investigation of supersaturation and in vitro permeation of the poorly water soluble drug ezetimibe2018Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 117, s. 147-153Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The interplay between supersaturation, precipitation and permeation characteristics of the poorly water-soluble drug ezetimibe (EZ) was investigated. Supersaturation and precipitation characteristics of EZ in the presence of Caco-2 cells were compared to those in a cell-free environment. The effect of the water-soluble polymer polyvinyl pyrrolidone (PVP-K30) on the supersaturation, precipitation and transport of EZ was also investigated and the amount of drug taken up by Caco-2 cells was quantified.

    A one-compartment setup without Caco-2 cells (i.e. in the wells of cell-culture plates) was used to mimic a non-sink in vitro dissolution chamber. The two-compartment Caco-2 cell monolayer setup (with apical and basolateral compartments) was used to investigate how the absorption of EZ affects supersaturation. EZ in varying degrees of supersaturation (DS; 10, 20, 30 and 40) was introduced into the one-compartment setup or the apical chamber of the two-compartment setup. Samples were collected at specific times to determine supersaturation, precipitation and permeation. At the end of the study, Caco-2 cells were lysed and the intracellular amount of EZ was quantified.

    In the one-compartment setup, a high DS was associated with rapid precipitation. Supersaturation was maintained for longer time periods and precipitation was lower in the presence of Caco-2 cells. There were no significant differences in the absorption rate of the drug, even at high concentrations on the apical side. Permeability coefficients for all supersaturated solutions (i.e. DS 10–40) were significantly (p < 0.05) different from those when EZ was present in crystalline form. Both concentrations of PVP-K30 (i.e. 0.05% and 0.1% w/v) improved solubility and supersaturation of EZ when added to the apical side, however, the increase in absorption at the higher concentration was not proportional. The amount of intracellular EZ increased with increasing DS in the apical side, until the saturation limit was reached in the cells (i.e. at DS 30 and higher).

    This study demonstrated that precipitation of EZ could be overestimated when supersaturation was investigated without the implementation of an absorption compartment in vitro, both in the absence and in the presence of polymer.

  • 9.
    Srivastava, K.
    et al.
    Physics Department, University of Lucknow, Lucknow, India.
    Khan, E.
    Physics Department, University of Lucknow, Lucknow, India.
    Shimpi, Manishkumar
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Kemiteknik.
    Tandon, P.
    Physics Department, University of Lucknow, Lucknow, India.
    Sinha, K.
    Physics Department, University of Lucknow, Lucknow, India.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Molecular structure and hydrogen bond interactions of a paracetamol-4,4′-bipyridine cocrystal studied using a vibrational spectroscopic and quantum chemical approach2018Ingår i: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 20, nr 2, s. 213-222Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of the current study is to perform the structural and spectroscopic characterization of paracetamol-4,4′-bipyridine (PRA-BPY) cocrystal using infrared, Raman spectroscopy and density functional theory (DFT) calculations. To reveal the interactions between PRA and BPY, two models (monomer and dimer + PRA) of a cocrystal are designed and optimized using DFT with a 6-311G (d, p) basis set. An atoms in molecule study shows that the non-covalent interactions in particular hydrogen bonds involved in forming the cocrystal are moderate in nature. Natural bond orbital analysis of the second order perturbation theory of the Fock matrix suggests that interactions LP (1) N13 → π∗(C15-O16) and LP (1) N56 → σ∗(N13-H14) are responsible for the stabilization of the molecule. 

  • 10.
    Vuddanda, Parameswara Rao
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap. Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom.
    Alomari, Mustafa
    Department of Pharmaceutics, UCL School of Pharmacy, University College London.
    Dodoo, Cornelius C.
    Department of Pharmaceutics, UCL School of Pharmacy, University College London.
    Trenfield, Sarah J.
    Department of Pharmaceutics, UCL School of Pharmacy, University College London.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Basit, Abdul W.
    Department of Pharmaceutics, UCL School of Pharmacy, University College London.
    Gaisford, Simon
    Department of Pharmaceutics, UCL School of Pharmacy, University College London.
    Personalisation of warfarin therapy using thermal ink-jet printing2018Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 117, s. 80-87Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Warfarin is a widely used anticoagulant that is critical in reducing patient morbidity and mortality associated with thromboembolic disorders. However, its narrow therapeutic index and large inter-individual variability can lead to complex dosage regimes. Formulating warfarin as an orodispersible film (ODF) using thermal ink-jet (TIJ) printing could enable personalisation of therapy to simplify administration. Commercial TIJ printers are currently unsuitable for printing the milligram dosages, typically required for warfarin therapy. As such, this study aimed to modify a commercial TIJ printing system to formulate personalised warfarin ODFs containing therapeutic dosages. A TIJ printer was modified successfully with the printer functionality intact; the substrate (paper) rolling mechanism of the printer was replaced by printing onto a stationary stage. Free film substrates were composed of hydroxypropyl methylcellulose (20%w/w) and glycerol (3%w/w). The resulting ODFs were characterised for morphology, disintegration, solid-state properties and drug content. Printed film stability was assessed at 40 °C/75% relative humidity for 30 days. Therapeutic warfarin doses (1.25 and 2.5 mg) were successfully printed onto the film substrates. Excellent linearity was observed between the theoretical and measured dose by changing the warfarin feed concentration (R2 = 0.9999) and length of the print objective, i.e. the Y-value, (R2 = 0.9998). Rapid disintegration of the ODFs was achieved. As such, this study successfully formulated personalised warfarin ODFs using a modified TIJ printer, widening the range of applications for TIJ printing to formulate narrow therapeutic index drugs.

  • 11.
    Persson, Ann-Sofie
    et al.
    Department of Pharmacy, Uppsala University.
    Ahmed, Hamzah
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Alderborn, Göran
    Department of Pharmacy, Uppsala University.
    Powder compression properties of paracetamol, paracetamol hydrochloride, paracetamol cocrystals and coformers2018Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 107, nr 7, s. 1920-1927Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective was to study the relationship between crystal structure, particle deformation properties and tablet-forming ability for the monoclinic form of paracetamol (PRA), two cocrystals and a salt crystal of PRA in addition to two coformers (oxalic acid and 4,4’-bipyridine). Thus, the structure – property – performance relationship was investigated. Analytical powder compression was used for determination of effective plasticity, as inferred from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was determined from in-die tablet elastic recovery.

    plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag layers displayed similar plasticity as cThe rystals containing slip planes. In addition, crystals containing slip-planes displayed both high and low plasticity.

    The mechanical properties could neither be linked to the tablet-forming ability as the tablet tensile strength, unexpectedly, displayed a tendency to reduce with increased plasticity stiffness. Furthermore, the elastic deformation could not explain the tablet forming ability.

    It was concluded that no relationship between structure – property – performance for paracetamol and its cocrystals and salt could be established. Thus, it was indicated that to establish such a relationship an improved knowledge of crystallographic structure and inter-particle bonding during compaction is needed.

  • 12.
    Fritz, Hans F.
    et al.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile.
    Ortiz, Andrea C.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Morales, Javier O.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap. Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile.
    Preparation of a novel lipid-core micelle using a low-energy emulsification method2018Ingår i: Drug Delivery and Translational Research, ISSN 2190-393X, Vol. 8, nr 6, s. 1807-1814Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    High-energy methods for the manufacturing of nanomedicines are widely used; however, interest in low-energy methods is increasing due to their simplicity, better control over the process, and energy-saving characteristics during upscaling. Here, we developed a novel lipid-core micelle (LCM) as a nanocarrier to encapsulate a poorly water-soluble drug, nifedipine (NFD), by hot-melt emulsification, a low-energy method. LCMs are self-assembling colloidal particles composed of a hydrophobic core and a hydrophilic shell. Hybrid materials, such as Gelucire 44/14, are thus excellent candidates for their preparation. We characterized the obtained nanocarriers for their colloidal properties, drug loading and encapsulation efficiency, liquid state, stability, and drug release. The low-energy method hot-melt emulsification was successfully adapted for the manufacturing of small and narrowly dispersed LCMs. The obtained LCMs had a small average size of ~ 11 nm and a narrow polydispersity index (PDI) of 0.228. These nanocarriers were able to increase the amount of NFD dispersible in water more than 700-fold. Due to their sustained drug release profile and the PEGylation of Gelucire 44/14, these nanocarriers represent an excellent starting point for the development of drug delivery systems designed for long circulation times and passive targeting.

  • 13.
    Alomari, Mustafa
    et al.
    UCL School of Pharmacy, University College London.
    Vuddanda, Parameswara Rao
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap. UCL School of Pharmacy, University College London.
    Trenfield, Sarah J.
    UCL School of Pharmacy, University College London.
    Dodoo, Cornelius C.
    UCL School of Pharmacy, University College London.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Basit, Abdul W.
    UCL School of Pharmacy, University College London.
    Gaisford, Simon
    UCL School of Pharmacy, University College London.
    Printing of T3 and T4 Oral Drug Combinations as a Novel Strategy for Hypothyroidism2018Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, nr 1-2, s. 363-369Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypothyroidism is a chronic and debilitating disease that is estimated to affect 3% of the general population. Clinical experience has highlighted the synergistic value of combining triiodothyronine (T3) and thyroxine (T4) for persistent or recurrent symptoms. However, thus far a platform that enables the simultaneous and independent dosing of more than one drug for oral administration has not been developed. Thermal inkjet (TIJ) printing is a potential solution to enable the dual deposition of T3 and T4 onto orodispersible films (ODFs) for therapy personalisation. In this study, a two-cartridge TIJ printer was modified such that it could print separate solutions of T3 and T4. Dose adjustments were achieved by printing solutions adjacent to each other, enabling therapeutic T3 (15–50 μg) and T4 dosages (60–180 μg) to be successfully printed. Excellent linearity was observed between the theoretical and measured dose for both T3 and T4 (R2 = 0.982 and 0.985, respectively) by changing the length of the print objective (Y-value). Rapid disintegration of the ODFs was achieved (< 45 seconds). As such, this study for the first time demonstrates the ability to produce personalised dose combinations by TIJ printing T3 and T4 onto the same substrate for oral administration.

  • 14.
    Taylor, David M.
    et al.
    Maudsley Hospital, London, United Kingdom; King's College London Institute of Pharmaceutical Science, London, United Kingdom.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Werneke, U.
    Sunderby Research Unit, Umeå University, Umeå.
    Reducing the stigma of long acting injectable antipsychotics: current concepts and future developments2018Ingår i: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 72, nr S1, s. S36-S39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Long acting injectable antipsychotics (LAI-APs) are considered a major advance in psychiatric treatment concerning treatment adherence and outcomes. Yet, both, doctors and patients remain sceptical. Aim: To explain the rationale for using LAI-APs, review their effectiveness and explore barriers to use. Method: Clinical overview of LAI-APs from the patient and doctor’s perspective. Results: LAI-APs were developed to increase adherence to treatment, thereby improving treatment outcomes. LAI-APs may reduce the risk of relapse and hospitalisation. Yet, the evidence from the few meta-analyses available remains weak. Both patients and doctors may associate LAI-APs with stigma and coercion. Current means of improving adherence include more focus on the therapeutic relationship, better information, adverse effects minimisation and half-life extension of LAI-APs. Future means of improving adherence include novel administration techniques that abolish the need for injection. Conclusions: For both, clinicians and drug developers, drug adherence remains a major target for improving treatment outcomes. 

  • 15.
    Shimpi, Manishkumar R.
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Al-Hayali, Amani
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Cavanagh, Katie L.
    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor.
    Rodríguez- Hornedo, Nair
    Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor.
    Velaga, Sitaram P.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Tadalafil-malonic acid cocrystal: Physicochemical characterization, pH-solubility and supersaturation studies2018Ingår i: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 18, nr 8, s. 4378-4387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this study was to enhance the solubility and dissolution of a poorly water-soluble drug, tadalafil (TDF), by cocrystal formation with malonic acid (MOA), to characterize the cocrystal structure, and to quantify the cocrystal solution behavior. The crystal structure revealed a 1:1 stoichiometry wherein the TDF molecules form a double layered structure through N–H…O=C interactions linked to a catemeric chain of MOA molecules via O-H…O hydrogen bonds. Cocrystal solubility advantage (SA defined as Scocrystal/Sdrug) or supersaturation index was determined from eutectic point measurements to be 102 to 129 in the pH range of 1 to 3. Cocrystal dissolution generated supersaturation levels (Cmax/Sdrug) of 30 in buffer and 120 in the presence of a nucleation inhibitor, HPMC. The amorphous form of TDF generated supersaturation 3 times lower than cocrystal in buffer, and not significantly different from cocrystal in the presence of HPMC. Thus, supersaturation index is a valuable metric for assessing the risk of cocrystal conversion during kinetic studies and for predicting conditions when the usage of a precipitation inhibitor may significantly increase cocrystal exposure levels.

  • 16.
    Montenegro-Nicolin, Miguel
    et al.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago.
    Reyes, Patricio E.
    Instituto de Salud Pública de Chile, Santiago.
    Jara, Miguel O.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago.
    Vuddanda, Parameswara Rao
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Neira-Carrillo, Andrónico
    Advanced Center for Chronic Diseases (ACCDiS), Santiago.
    Butto, Nicole
    Advanced Center for Chronic Diseases (ACCDiS, )Santiago.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Morales, Javier O.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap. Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, Santiago.
    The Effect of Inkjet Printing over Polymeric Films as Potential Buccal Biologics Delivery Systems2018Ingår i: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 19, nr 8, s. 3376-3387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The buccal mucosa appears as a promissory route for biologic drug administration, and pharmaceutical films are flexible dosage forms that can be used in the buccal mucosa as drug delivery systems for either a local or systemic effect. Recently, thin films have been used as printing substrates to manufacture these dosage forms by inkjet printing. As such, it is necessary to investigate the effects of printing biologics on films as substrates in terms of their physical and mucoadhesive properties. Here, we explored solvent casting as a conventional method with two biocompatible polymers, hydroxypropyl methylcellulose, and chitosan, and we used electrospinning process as an electrospun film fabrication of polycaprolactone fibers due to its potential to elicit mucoadhesion. Lysozyme was used as biologic drug model and was formulated as a solution for printing by thermal inkjet printing. Films were characterized before and after printing by mechanical and mucoadhesive properties, surface, and ultrastructure morphology through scanning electron microscopy and solid state properties by thermal analysis. Although minor differences were detected in micrographs and thermograms in all polymeric films tested, neither mechanical nor mucoadhesive properties were affected by these differences. Thus, biologic drug printing on films was successful without affecting their mechanical or mucoadhesive properties. These results open way to explore biologics loading on buccal films by inkjet printing, and future efforts will include further in vitro and in vivo evaluations.

  • 17.
    Montero-Padilla, Soledad
    et al.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, 8380494, Santiago.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Morales, Javier O.
    Department of Pharmaceutical Science and Technology, School of Chemical and Pharmaceutical Sciences, University of Chile, 8380494, Santiago.
    Buccal Dosage Forms: general Considerations for Pediatric Patients2017Ingår i: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 18, nr 2, s. 273-282Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of an appropriate dosage form for pediatric patients needs to take into account several aspects, since adult drug biodistribution differs from that of pediatrics. In recent years, buccal administration has become an attractive route, having different dosage forms under development including tablets, lozenges, films, and solutions among others. Furthermore, the buccal epithelium can allow quick access to systemic circulation, which could be used for a rapid onset of action. For pediatric patients, dosage forms to be placed in the oral cavity have higher requirements for palatability to increase acceptance and therapy compliance. Therefore, an understanding of the excipients required and their functions and properties needs to be particularly addressed. This review is focused on the differences and requirements relevant to buccal administration for pediatric patients (compared to adults) and how novel dosage forms can be less invasive and more acceptable alternatives. 

  • 18.
    Al-Hayali, Amani Ibraheem Younis
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Tavellin, Staffan
    Departments of Pharmacology and Clinical Neuroscience, Umeå university.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media2017Ingår i: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, nr 1, s. 79-88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25˚C and 37˚C) were investigated in this work. Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry, modulated differential scanning calorimetry, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions. All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25˚C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried solid (SD) dispersions and supersaturation was maintained. However, at 37˚C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures. Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25˚C may not predict the supersaturation behavior at physiologically relevant temperatures.  

  • 19.
    Rao Vuddanda, Parameswara
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Montenegro-Nicolini, Miguel
    Department of Pharmaceutical Sciences and Technology, University of Chile, Santiago.
    Morales, Javier O.
    Department of Pharmaceutical Sciences and Technology, University of Chile, Santiago.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Effect of plasticizers on the physico-mechanical properties of pullulan based pharmaceutical oral films2017Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, s. 290-298Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effect of different plasticizers (glycerol, vitamin E TPGS and triacetin) and their concentrations on the physico-mechanical properties of pullulan based oral films was studied. A full factorial (32) design of experiments was used. Elastic modulus, tensile strength, elongation at break and disintegration time were selected as response variables. Modulated differential scanning calorimeter (MDSC) was used for determining glass transition temperature (Tg) of pullulan films. The surface morphology of films was evaluated by SEM, while ATR-FTIR was used to obtain a molecular level understanding of polymer-plasticizer interactions. The DoE analysis allowed for the modelling of tensile strength and elongation at break. The highest elongations were observed in glycerol at 20% w/w. Majority of the films disintegrated within one minute without significant differences. ATR-FTIR spectra of pullulan alone and different plasticizer blend films show characteristic molecular interactions. The present study concluded that glycerol is suitable plasticizer compared to others for manufacturing pullulan based oral films.

  • 20.
    Rao Vuddanda, Parameswara
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Montenegro-Nicolini, Miguel
    Department of Pharmaceutical Sciences and Technology, University of Chile.
    Morales, Javier O.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Effect of surfactants and drug load on physico-mechanical and dissolution properties of nanocrystalline tadalafil-loaded oral films2017Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 109, s. 372-380Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the present work was to prepare tadalafil (TDF) nanocrystals-loaded oral polymeric films (OFs) and investigate the effect of hydrophilic surfactants and drug loads on the physico-mechanical and dissolution properties. The nanosuspensions of TDF were prepared by high shear homogenization. HPMC based placebo casting film gel was prepared and mixed with TDF nanosuspensions. Films were casted using an automated film applicator and dried at 60 °C for 45 min. Particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of TDF nanosuspensions were measured in a Zetasizer. The films were characterized using SEM, AFM, DSC, TGA and PXRD. The mechanical properties and in vitro drug release were determined using standard methods. TDF existed in crystalline form and the particles remained in the nano-range in redispersed films. TDF nanocrystals were embedded in the polymeric matrix and the drug loaded films were rough on the surface. Mechanical properties of the films varied with changes in drug load and surfactant. Significant changes in the disintegration times were noticed in films containing surfactants compared to surfactant-free films. About 80% of the drug release was observed between 3 and 30 min. TPGS showed better TDF release from the films at different drug loads

  • 21.
    Malamatari, Maria
    et al.
    Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent .
    Ross, Steven A.
    Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent .
    Douroumis, Dennis
    Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent .
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Experimental cocrystal screening and solution based scale-up cocrystallization methods2017Ingår i: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 117, s. 162-177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cocrystals are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. If one of the components is an active pharmaceutical ingredient (API), the term pharmaceutical cocrystal is often used. There is a growing interest among drug development scientists in exploring cocrystals, as means to address physicochemical, biopharmaceutical and mechanical properties and expand solid form diversity of the API. Conventionally, coformers are selected based on crystal engineering principles, and the equimolar mixtures of API and coformers are subjected to solution-based crystallization that are commonly employed in polymorph and salt screening. However, the availability of new knowledge on cocrystal phase behaviour in solid state and solutions has spurred the development and implementation of more rational experimental cocrystal screening as well as scale-up methods. This review aims to provide overview of commonly employed solid form screening techniques in drug development with an emphasis on cocrystal screening methodologies. The latest developments in understanding and the use of cocrystal phase diagrams in both screening and solution based scale-up methods are also presented. Final section is devoted to reviewing the state of the art research covering solution based scale-up cocrystallization process for different cocrystals besides more recent continuous crystallization methods.

  • 22.
    Al-Hayali, Amani
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Selo, Mohammed Ali
    School of Pharmacy and Pharmaceutical Sciences , Trinity College Dublin .
    Ehrhardt, Carsten
    School of Pharmacy and Pharmaceutical Sciences , Trinity College Dublin .
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Investigation of supersaturation and permeation of a poorly water soluble drug Ezetimibe: Systems approaches to drug discovery, development and clinical usage2017Ingår i: Future Medicines For One World, 2017Konferensbidrag (Refereegranskat)
  • 23.
    Trubetskaya, Anna
    et al.
    Luleå tekniska universitet, Institutionen för teknikvetenskap och matematik, Energivetenskap.
    Beckmann, Gert
    Retsch Technology GmbH.
    Wadenbäck, Johan
    Amager power plant, HOFOR A/S.
    Holm, Jens Kai
    DONG Energy Thermal Power A/S.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Weber, Roman
    Institute of Energy Processes Engineering and Fuel Technology, Clausthal University of Technology.
    One way of representing the size and shape of biomass particles in combustion modeling2017Ingår i: Fuel, ISSN 0016-2361, E-ISSN 1873-7153, Vol. 206, s. 675-683Artikel, recension (Refereegranskat)
    Abstract [en]

    This study aims to provide a geometrical description of biomass particles that can be used in combustion models. The particle size of wood and herbaceous biomass was compared using light microscope, 2D dynamic imaging, laser diffraction, sieve analysis and focused beam reflectance measurement. The results from light microscope and 2D dynamic imaging analysis were compared and it showed that the data on particle width, measured by these two techniques, were identical. Indeed, 2D dynamic imaging was found to be the most convenient particle characterization method, providing information on both the shape and the external surface area. Importantly, a way to quantify all three dimensions of biomass particles has been established. It was recommended to represent a biomass particle in combustion models as an infinite cylinder with the volume-to-surface ratio (V/A) measured using 2D dynamic imaging.

  • 24.
    Shimpi, Manishkumar
    et al.
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Kemiteknik.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Shah, Faiz Ullah
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Kemiteknik.
    Antzutkin, Oleg
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Kemiteknik.
    Pharmaceutical Crystal Engineering Using Ionic Liquid Anion–Solute Interactions2017Ingår i: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 17, nr 4, s. 1729-1734Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The main purpose of this work was to investigate the potential of ionic liquids (ILs) in crystal engineering. We have employed ILs with different combinations of cations and anions to study their role in directing crystal structure formation of a nicotinamide (NIC) and oxalic acid (OXA) system. A new crystal form of NIC–OXA salt (2:1) was identified and characterized using standard solid state tools such as powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Raman and infrared spectroscopy. The crystal structure of the 2:1 salt was elucidated using single-crystal X-ray diffraction. The NIC–OXA 2:1 salt form revealed a two-dimensional layered structure, while the known 1:1 salt had a perpendicular “tape-like” structure. The 2:1 salt form could only be crystallized from the ILs possessing hydrogen bond acceptor functionality. We demonstrated that specific ILs could be selected as solvents for altering the solid-state structure of organic and inorganic materials.

  • 25.
    Ahmed, Hamzah
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Shimpi, Manishkumar R.
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Kemiteknik.
    Velaga, Sitaram P.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol2017Ingår i: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, nr 1, s. 89-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives were to study mechanical properties of various solid forms of paracetamol and relate to their crystal structures. Paracetamol Form I (PRA), its cocrystals with oxalic acid (PRA-OXA) and 4,4-bipyridine (PRA-BPY) and hydrochloride salt (PRA-HCL) were selected. Cocrystals and salt were scaled-up using rational crystallization methods. The resulting materials were subjected to differential scanning solid-state characterization. The powders were sieved and 90-360 µm sieve fraction was considered. These powders were examined by scanning electron microscopy (SEM) and densities were determined. Tablets were made at applied pressures of 35-180 MPa under controlled conditions and the tablet height, diameter and hardness were measured. Tensile strength and porosity of the tablets were estimated using well known models. Crystal structures of these systems were visualized and slips planed were identified. Cocrystal and salt of PRA were physically pure. Sieved powders had comparable morphologies and particle size. The apparent and theoretical densities of powders were similar but no clear trends were observed. The tensile strengths of these compacts were increased with increasing pressure whereas tabletability decreased in the order oxalic acid > PRA-HCL ≈ PRA-OXA > BPY > PRA-BPY. Tablet tensile strength decreases exponentially with increasing porosity with the exception of PRY-BPY and BPY. Slip plane prediction based on attachment energies may not be independently considered. However, it was possible to explain the improved mechanical properties of powders based on the crystal structure. Cocrystallization and salt formation have introduced structural features that are responsible for improved tableting properties of PRA.

  • 26.
    Vuddanda, Parameswara Rao
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Singh, Sanjay
    Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanas.
    Boswellic acid: medicinal use of an ancient herbal remedy2016Ingår i: Journal of Herbal Medicine, ISSN 2210-8033, Vol. 6, nr 4, s. 163-170Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Boswellic acid (BA) is an ancient herbal drug prescribed in the Indian traditional medicine systems (Ayurveda) for treatment of coughs, colds, hoarseness, bronchitis, asthma, dyspnea and diarrhea. Current research suggests it also has therapeutic potential in modern medical practice. Therefore, it is of interest to the research community to consolidate the preclinical and clinical findings on BA. The aim of this review was to comprehensively cover the plant sources, phytochemistry and physicochemical properties of BA along with its medicinal properties, safety, toxicity, and regulatory status. The review also discussed the challenges associated with drug delivery and some feasible approaches for addressing these. Four electronic databases (Scifinder, Unbound Medline, PubMed and Science Direct) and two internet search engines (Scirus and Google Scholar) were extensively searched without any time constraint.The many studies discussed in the review indicated therapeutic potential for BA in the treatment of a range of chronic diseases including arthritis, cancer, asthma and diabetes. It is hoped that this review will help researchers identify relevant research questions leading to the development of effective formulations and a better understanding of the safety of BA, with the aim of promoting it as a mainstream treatment for various diseases in clinical practice. 

  • 27.
    Prajapati, Preeti
    et al.
    Physics Department, University of Lucknow.
    Pandey, Jaja
    Physics Department, University of Lucknow.
    Shimpi, Manishkumar
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Srivastava, Anubha
    Physics Department, University of Lucknow.
    Tandon, Poonam
    Physics Department, University of Lucknow.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Sinha, Kirti
    Physics Department, University of Lucknow.
    Combined spectroscopic and quantum chemical studies of ezetimibe2016Ingår i: Journal of Molecular Structure, ISSN 0022-2860, E-ISSN 1872-8014, Vol. 1125, s. 193-203Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ezetimibe (EZT) is a hypocholesterolemic agent used for the treatment of elevated blood cholesterol levels as it lowers the blood cholesterol by blocking the absorption of cholesterol in intestine. Study aims to combine experimental and computational methods to provide insights into the structural and vibrational spectroscopic properties of EZT which is important for explaining drug substance physical and biological properties. Computational study on molecular properties of ezetimibe is presented using density functional theory (DFT) with B3LYP functional and 6-311++G(d,p) basis set. A detailed vibrational assignment has been done for the observed IR and Raman spectra of EZT. In addition to the conformational study, hydrogen bonding and molecular docking studies have been also performed. For conformational studies, the double well potential energy curves have been plotted for the rotation around the six flexible bonds of the molecule. UV absorption spectrum was examined in methanol solvent and compared with calculated one in solvent environment (IEF-PCM) using TD-DFT/6-31G basis set. HOMO-LUMO energy gap of both the conformers have also been calculated in order to predict its chemical reactivity and stability. The stability of the molecule was also examined by means of natural bond analysis (NBO) analysis. To account for the chemical reactivity and site selectivity of the molecules, molecular electrostatic potential (MEPS) map has been plotted. The combination of experimental and calculated results provide an insight into the structural and vibrational spectroscopic properties of EZT. In order to give an insight for the biological activity of EZT, molecular docking of EZT with protein NPC1L1 has been done.

  • 28.
    Velaga, Sitaram
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Nikjoo, Dariush
    Luleå tekniska universitet, Institutionen för teknikvetenskap och matematik, Materialvetenskap.
    Rao Vuddanda, Parameswara
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Drying Kinetics of Polymeric Films: theoretical and experimental studies2016Konferensbidrag (Refereegranskat)
  • 29.
    Vuddanda, Parameswara Rao
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Mathew, Aji P.
    Luleå tekniska universitet, Institutionen för teknikvetenskap och matematik, Materialvetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Electrospun nanofiber Mats for ultrafast release of ondansetron2016Ingår i: Reactive & functional polymers, ISSN 1381-5148, E-ISSN 1873-166X, Vol. 99, s. 65-72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nanofiber mats or films are promising platforms that can offer unique opportunities in oromucosoal drug delivery. However, the conventional film forming technologies are unable to produce mats with unique internal microstructure and properties. Thus, the present study was aimed to develop electrospun nanofiber mats of a model drug -ondansetron hydrochloride (OND) for ultrafast drug release. Polyvinyl alcohol (PVA), a water soluble synthetic polymer was used in the preparation of nanofiber mats and casting film. The OND nanofiber mats and conventional films were prepared by electrospinning and casting methods, respectively. Different electrospinning process variables (feed rate, electric voltage and tip to collector distance) were investigated. Nanofiber mats and casted films were characterized using Scanning electron microscopy (SEM), Atomic force microscopy (AFM), Differential scanning calorimetry (DSC), Powder X-ray diffraction (PXRD), and Attenuated total reflection – Fourier transform infrared spectroscopy (ATR-FTIR). The folding endurance, drug content, wetting behaviour and disintegration properties and in-vitro drug release studies were also performed.The SEM and AFM had revealed that the nanofiber mats were formed with smooth uniform texture. Solid state studies indicated that the OND was in amorphous state and uniformly dispersed in PVA mats and a film. The electrospun nanofiber mat and casted film of OND showed sufficient mechanical properties. Wet sponge method suggested that OND nanofiber mats were simultaneously wetted and disintegrated within 10 s, which is ultrafast compared to casted films. The total amount of OND was released in 90 s (1.5 min) and 1800 s (30 min) from OND-PVA electrospun nanofiber mats and casted film, respectively. OND nanofiber mats can be promising alternatives to existing solid dosage forms for ultrafast release of drugs.

  • 30.
    Singh, Sanjay Kumar
    et al.
    Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanas.
    Dadhania, Parth
    Pharma Research, Lupin Limited (Research Park), Pune.
    Vuddanda, Parameswara Rao
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Jain, Achint K.
    Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanas.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Singh, Sanjay
    Department of Pharmaceutics, Indian Institute of Technology, Banaras Hindu University, Varanas.
    Intranasal delivery of asenapine loaded nanostructured lipid carriers: formulation, characterization, pharmacokinetic and behavioural assessment2016Ingår i: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, nr 3, s. 2032-2045Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the present research work was to develop asenapine (ASM) loaded nanostructured lipid carriers (ANLC) for the delivery of drugs in the brain by an intranasal route to enhance therapeutic efficacy. A quality by design approach was used for development and optimization of ANLC. A total of five independent variables were selected, in which three were compositions and two were process variables, while particle size and entrapment efficiency were selected as response variables. The final optimized batch was evaluated by various in vitro characterizations as well as in vivo brain and plasma pharmacokinetic studies. Finally, the ANLC was assessed for efficacy and safety profiling for upto three weeks by a behavior model viz. catalepsy, induced locomotor and paw test in Charles Foster rats. The observed particle size, entrapment efficiency and zeta potential of ANLC was found to be 167.30 +/- 7.52 nm, 83.50 +/- 2.48% and -4.33 +/- 1.27 mV, respectively. Surface characterization studies demonstrated a spherical shape with a smooth surface of ANLC which follows the Korsmeyer-Peppas in vitro release kinetic model (r(2) = 0.9911, n = 0.53). A brain pharmacokinetic study indicated a significantly higher (p < 0.05) peak drug concentration (C-max: 74.13 +/- 6.73 ng mL(-1)), area under the drug concentration-time curve (AUC(0-24) (h): 560.93 +/- 27.85 h ng mL(-1)) and mean residence time (MRT: 7.1 +/- 0.13 h) of ANLC compared to ASM in the brain via an intranasal route. The results of behaviour studies of ANLC showed a significant decrease in extra-pyramidal side effects with increasing antipsychotic effect after 1-2 week(s) of treatment. These findings demonstrate that nanostructured lipid carriers could be a new promising drug delivery system for intranasal delivery of asenapine in the treatment of schizophrenia

  • 31.
    Pandey, Jaya
    et al.
    Physics Department, University of Lucknow.
    Prajapati, Preeti
    Physics Department, University of Lucknow.
    Shimpi, Manishkumar
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Tandon, Poonam
    Physics Department, University of Lucknow.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Srivastava, Anubha
    Physics Department, University of Lucknow.
    Sinha, Kirti
    Physics Department, University of Lucknow.
    Studies of molecular structure, hydrogen bonding and chemical activity of a nitrofurantoin-L-proline cocrystal: a combined spectroscopic and quantum chemical approach2016Ingår i: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, nr 78, s. 74135-74154Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nitrofurantoin (NTF) has been used as an antibacterial drug to treat bacterial infections of the urinary tract. The purpose of this work is to predict the hydrogen bonds (potential synthons) present in the cocrystal of nitrofurantoin-L-proline (NTF-LP) through a computational approach (DFT calculations) and validate using vibrational spectroscopic studies. The present study illustrates the formation and characterization of the cocrystal of NTF-LP. The molecular structure of the NTF-LP cocrystal has been predicted by forming several models on the basis of the hydrogen bonding patterns observed in other NTF cocrystals. A conformational study and potential energy surface scan have been plotted around three flexible bonds of the cocrystal molecule and two stable conformers have been obtained. NBO analysis of the second order perturbation theory of the Fock matrix suggests that interaction n1O(39) → σ*(N13–H21) is responsible for the stabilization of the molecule. Quantum theory of atoms in molecules (QTAIM) explains that all interactions are medium and partially covalent in nature as ∇2ρBCP > 0, HBCP < 0. The molecular electrostatic potential surface (MEPS) of the cocrystal has been visualized for its most electropositive potential in the region of the NH2+ group and most electronegative potential in the vicinity of the COO− group. The HOMO and LUMO energies and electronic charge transfer (ECT) confirms that charge flows from the co-former (LP) to NTF (API). Local reactivity descriptor parameters have been used to predict the reactive sites of the cocrystal and global reactivity descriptor parameters suggest that the cocrystal is softer thus more reactive in comparison to NTF. The experimental and theoretical results support the formation of the cocrystal through the strong hydrogen bond present between the NH group of NTF and carboxylate COO− group of LP and shows that LP is present in the zwitterionic form.

  • 32.
    Srivastava, Karnica
    et al.
    Physics Department, University of Lucknow.
    Shimpi, Manishkumar
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Srivastava, Anubha
    Physics Department, University of Lucknow.
    Tandon, Poonam
    Physics Department, University of Lucknow.
    Sinha, Kirti
    Physics Department, University of Lucknow.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Vibrational analysis and chemical activity of paracetamol-oxalic acid cocrystal based on monomer and dimer calculations: DFT and AIM approach2016Ingår i: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, nr 12, s. 10024-10037Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The study of structural and spectral characteristics of a paracetamol-oxalic acid (PRA-OXA) cocrystal has been carried out using two models (monomer and dimer), with the aim to understand the supramolecular structure and intramolecular interactions within the cocrystal. The cocrystal has been characterized by infrared and Raman spectroscopy combined with quantum chemical calculations molecular electrostatic potential surface (MEPS), frontier orbital analysis and electronic reactivity descriptors were used to understand the role of interactions involved in affecting the chemical reactivity of individual molecules in the cocrystal. It is observed that the C=O, N-H and O-H groups of paracetamol are involved in hydrogen bonds to form cocrystals. NBO analysis suggests that the two types of interactions LP(1)(N8) -> pi*(C9-O10) and LP(2)(O10) -> sigma*(O25-H28) are responsible for the stability of the molecule. AIM analysis suggested that the non-covalent interactions are moderate in nature. The calculated HOMO-LUMO energies reveal that the charge transfer occurs within the cocrystal. Chemical reactivity parameters show that the cocrystal is more active than paracetamol.

  • 33.
    Cho, Wonkyung
    et al.
    College of Pharmacy, Yonsei University.
    Kim, Min-Soo
    College of Pharmacy, Pusan National University.
    Jung, Min-Sook
    College of Pharmacy, Chungnam National University.
    Park, Junsung
    College of Pharmacy, Yonsei University.
    Cha, Kwang-Ho
    College of Pharmacy, Yonsei University.
    Kim, Jeong-Soo
    College of Pharmacy, Chungnam National University.
    Alhalaweh, Amjad
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Park, Hee Jun
    College of Pharmacy, Chungnam National University.
    Hwang, Sung-Joo
    College of Pharmacy, Chungnam National University.
    Design of salmon calcitonin particles for nasal delivery using spray-drying and novel supercritical fluid-assisted spray-drying processes2015Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 478, nr 1, s. 288-296Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The overall aim of this study was to prepare a nasal powder formulation of salmon calcitonin (sCT) using an absorption enhancer to improve its bioavailability. In this work, powder formulations for nasal delivery of sCT were studied using various absorption enhancers and stabilizers. Powders were prepared by two different methods: conventional spray-drying (SD) and novel supercritical fluid-assisted spray-drying (SASD) to investigate the role of CO2 in the particle formation process. The prepared sCT powder formulations were characterized by several analyses; powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), and the Fourier transform infrared (FT-IR) spectroscopy method. The particle size distribution was also evaluated. In vivo absorption tests were carried out in Sprague-Dawley rat using the prepared powder formulations, and the results were compared to those of raw sCT. Quantitative analysis by high-performance liquid chromatography (HPLC) indicated that sCT was chemically stable after both the SD and SASD processes. Results of PXRD, SEM, and FT-IR did not indicate a strong interaction or defragmentation of sCT. The in vivo absorption test showed that SD- and SASD-processed sCT powders increased the bioavailability of the drug when compared to the nasal administration of raw sCT. In addition, SASD-processed sCT exhibited higher nasal absorption when compared with SD-processed sCT in all formulations due to a reduction of particle size. The results from this study illustrate that the preparation of nasal powders using the SASD process could be a promising approach to improve nasal absorption of sCT.

  • 34.
    Padrela, Luis
    et al.
    Department of Chemical and Biological Engineering, Instituto Superior Técnico, Lisboa.
    Rodrigues, Miguel A.
    Department of Chemical and Biological Engineering, Instituto Superior Técnico, Lisboa, Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Tiago, João
    Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Matos, Henrique A.
    Department of Chemical and Biological Engineering, Instituto Superior Técnico, Lisboa, Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Azevedo, Edmundo Gomes de
    Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Department of Chemical and Biological Engineering, Instituto Superior Técnico, Lisboa.
    Insight into the Mechanisms of Cocrystallization of Pharmaceuticals in Supercritical Solvents2015Ingår i: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 15, nr 7, s. 3175-3181Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Carbon dioxide has been extensively used as a green solvent medium for the crystallization of active pharmaceutical ingredients (APIs) by replacing harmful organic solvents. This work explores the mechanisms underlying a novel recrystallization method-cocrystallization with supercritical solvent (CSS)-which enables APIs cocrystallization by suspending powders in pure CO2. Six well-known APIs that form cocrystals with saccharin (SAC) were processed by CSS, namely, theophylline (TPL), indomethacin (IND), carbamazepine (CBZ), caffeine (CAF), sulfamethazine (SFZ), and acetylsalicylic acid (ASA). Pure cocrystals were obtained for TPL, IND, and CBZ (with SAC) after 2 h of CSS processing. Convection was revealed to be a determining parameter for successful cocrystallization with high-yield levels. TPL-SAC was selected as a model system to study the cocrystallization kinetics in the gas, supercritical, and liquid phases under different conditions of pressure (8-20 MPa), temperature (30 to 70 degrees C), and convection regimes. The solubility of each substance in CO2 was measured at the selected working conditions. TPL-SAC showed a cocrystallization rate of 2.9% min(-1), two times higher than that of IND-SAC, due to the higher solubility of TPL in CO2. The cocrystallization kinetics was also improved by increasing the CO2 density, showing that cocrystallization was limited by the dissolution of cocrystal formers. Overall, the CSS process has a potential for scale-up as a novel, simple, solvent-free batch process whenever the cocrystal phase is formed in the CO2 media.

  • 35.
    Llinas, Antonio
    et al.
    R&D AstraZeneca, Respiratory, Inflammation and Autoimmune iMed.
    Barbas, Rafael
    Unitat de Polimorfisme i Calorimetria and Unitat de Difracció de Raigs X, Centres Científics i Tecnològics, Universitat de Barcelona.
    Font-Bardia, Merce
    Unitat de Polimorfisme i Calorimetria and Unitat de Difracció de Raigs X, Centres Científics i Tecnològics, Universitat de Barcelona.
    Quayle, Michael J.
    R&D AstraZeneca, Global Medicines Development, Pharmaceutical Development.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Prohens, Rafel
    Unitat de Polimorfisme i Calorimetria and Unitat de Difracció de Raigs X, Centres Científics i Tecnològics, Universitat de Barcelona.
    Two New Polymorphic Cocrystals of Zafirlukast: Preparation, Crystal Structure, and Stability Relations2015Ingår i: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 15, nr 8, s. 4162-4169Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two new cocrystals of zafirlukast with piperazine, existing in five different solid forms, have been discovered during a cocrystal screening. The crystal structure of one of these form has been determined by single crystal X-ray diffraction, and the stability landscape of the crystalline forms of the new cocrystal has been studied. In the present article, we extend the knowledge about the solid state of this important pharmaceutical drug for the treatment of asthma by reporting the crystal structures of two new solvates (acetonitrile and butanol) and the elusive anhydrous Form X, which have been solved by single crystal X-ray diffraction

  • 36.
    Al-Hayali, Amani Ibraheem Younis
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Tavelin, Staffan
    Umeå university.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Dissolution and precipitation behavior of ternary solid dispersions of Ezetimibe in biorelevant media: AAPS annual meeting and Exposition2014 USA2014Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    PurposeTo prepare ternary solid dispersions of Ezetimibe (EZ) and investigate their powder dissolution and precipitation behavior(supersaturation) in simulated gastric and intestinal fluidsMethodsTernary solid dispersions of EZ were prepared with PVPK30 and Poloxamer 188 at different ratios. Spray drying and meltquenching methods were used for the preparation of these solid dispersions. The solid dispersions were characterized bybasic to advanced solid-state tools including Modulated differential scanning calorimetry (MDSC), Powder X-ray diffractionand Fourier transform infrared spectroscopy .Biorelevant simulated media (FaSSIF pH 6.5 and FaSSGF pH1.6) were used tostudy the supersaturating solubility of the ternary solid dispersions. HPLC was used to determine the drug concentrationsResultsTernary solid dispersions were successfully prepared by spray drying and melt quench methods. All prepared soliddispersions showed broadening of the XRD peaks indicating amorphous nature. MDSC analysis revealed disappearance ofthe melting peak of Ezetimibe indicating that molecular dispersion of the drug in polymer matrix. The solid dispersions withhigher PVPK30 content showed single Tg at 158.54 °C (spray drying) and 169.32 °C (melt quench). About 10 folds increasein the apparent solubility was observed for solid dispersions prepared by both methods. However, melt quenched soliddispersions had maintained the supersaturation solubility in FaSSIF longer than spray dried solid dispersions. Dissolutionstudies in FaSSGF are ongoingConclusionAmorphous ternary solid dispersions of Ezetimibe containing PVP K30 and Poloxamer 188 could be prepared by spraydrying and melt quenching methods. These solid dispersions showed improved solubility and prolonged supersaturation inbiorelevant media

  • 37. Alhalaweh, Amjad
    et al.
    Ali, Hassan
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media2014Ingår i: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 14, nr 2, s. 643-648Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Capturing solubility advantages of cocrystals is of great interest, and thus to understand the mechanism by which different excipients could maintain the supersaturation generated by cocrystals at the course of absorption in aqueous media is essential. To achieve this aim, the impact of different excipients on dissolution behavior of indomethacin-saccharin (IND-SAC) were monitored by measuring the concentrations of cocrystal components in the absence and presence of various concentration of excipients by HPLC, and solid phases were analyzed by differential scanning calorimetry after each experiment and the potential of Raman spectroscopy for monitoring phase transformations in situ was tested. No dissolution advantage was offered by cocrystals in the absence of any solution additive. The polymer and surfactant used in the study increased the solubility of IND but not SAC. This differential solubilization effect is believed to have stabilized the cocrystals for a relevant period for the absorption to take place. This could be attributed to either decreased gap between supersaturation and saturation of the drug or drug interaction with the additives. Understanding the effects of excipients type and concentration on the transformation profile is vital for designing enabling formulations for cocrystals. The eutectic constant may be useful in selecting excipients for stabilizing cocrystals.

  • 38.
    Shimpi, Manishkumar
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap.
    Childs, Scott L.
    Renovo Research, Atlanta, GA.
    Boström, Dan
    Umeå universitet, Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    New cocrystals of ezetimibe with l-proline and imidazole2014Ingår i: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 16, nr 38, s. 8984-8993Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objectives of the study were to screen and prepare cocrystals of anti-cholesterol drug ezetimibe (EZT) with the aim of increasing its solubility and dissolution rate. Thermodynamic phase diagram based high throughput screening was performed using wet milling/grinding or solution crystallization methods. A large number of coformers were tested and the resulting solids were preliminarily characterized using X-ray powder diffraction (PXRD) and Raman spectroscopy. Potential cocrystals of EZT with l-proline and imidazole and a solvate formamide were identified in the screening experiments. The cocrystal hits were further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solution Proton nuclear magnetic resonance spectroscopy (1H-NMR) and single crystal XRD. The dissolution properties and stability of cocrystals were determined. Single-crystal X-ray diffraction data were obtained for EZT, EZT-IMI cocrystal and formamide solvate of ezetimibe. All three systems were crystallized in non-centrosymmetric orthorhombic space group P212121with Z = 4. Robust O-H⋯O, O-H⋯N, N-H⋯O and C-H⋯O hydrogen bonds played an important role in all these crystal structures. EZT-PRO cocrystal showed improved apparent solubility and solid state stability

  • 39.
    Chattoraj, Sayantan
    et al.
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Shi, Limin
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Chen, Miles
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Alhalaweh, Amjad
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Sun, Changquan Calvin
    Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota.
    Origin of Deteriorated Crystal Plasticity and Compaction Properties of a 1:1 Cocrystal between Piroxicam and Saccharin2014Ingår i: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 14, nr 8, s. 3864-3874Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The 1:1 cocrystal between piroxicam and saccharin exhibits significantly deteriorated powder compaction properties compared to both coformers. The molecular origin of this effect is revealed by a systematic investigation of crystal mechanical properties, probed with nanoindentation, and crystal structure analysis. The order of bulk powder tabletability of the three materials is identical to that of single crystal plasticity (saccharin > piroxicam > cocrystal). The lowest plasticity of the cocrystal is confirmed by its highest crystal hardness and the highest yield strength. The low plasticity of the cocrystal is attributed to structural packing features that discourage plastic deformation. This work demonstrates that cocrystallization, even though it may be useful to improve pharmaceutically relevant properties, must be carefully evaluated to avoid unexpected problems in formulation and drug product manufacturing due to compromised mechanical properties.

  • 40.
    Shayanfar, Ali
    et al.
    Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Jouyban, Abolghasem
    Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences.
    Solubility of carbamazepine, nicotinamide and carbamazepine-nicotinamide cocrystal in ethanol-water mixtures2014Ingår i: Fluid Phase Equilibria, ISSN 0378-3812, E-ISSN 1879-0224, Vol. 363, s. 97-105Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Solubility is an important physiochemical property of pharmaceutical compounds, and cocrystallization is one method used to improve the solubility of drugs. Carbamazepine is a drug from class II, according to the biopharmaceutical classification system, and it forms a cocrystal with nicotinamide. Carbamazepine cocrystallized with nicotinamide was synthesized using the solvent evaporation approach, and its characteristics were determined using differential scanning calorimetry and powder X-ray diffractometry. The solubility of various solid phases in ethanol. +. water mixtures was investigated at different temperatures using the shake-flask method, and the resulting precipitates were characterized. The solubility of carbamazepine was increased with the addition of ethanol up to a mass fraction of 0.8. Nevertheless, maximum solubility of NIC is observed in neat solvent (water). While the solubility of a cocrystal depends on the concentration of the coformer and its stability in the solution.

  • 41.
    Padrela, Luis
    et al.
    Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Rodrigues, Miguel A.
    Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Tiago, João Tiago
    Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Matos, Henrique A.
    Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Azevedo, Edmundo Gomes de
    Department of Chemical Engineering and Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa.
    Tuning physicochemical properties of theophylline by cocrystallization using the supercritical fluid enhanced atomization technique2014Ingår i: Journal of Supercritical Fluids, ISSN 0896-8446, E-ISSN 1872-8162, Vol. 86, s. 129-136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Formation of different micro- to nanosized cocrystals of theophylline is addressed by using the supercritical enhanced atomization (SEA) process. The experimental results presented here help to highlight how to prepare cocrystals of theophylline (TPL), using a supercritical fluid-based technique to accomplish the required physicochemical properties of that active pharmaceutical ingredient (API). The SEA process shows a strong versatility and feasibility towards the formation of highly pure theophylline cocrystals, using tetrahydrofuran as a solvent. The formation of TPL cocrystals with different types of morphology and dissolution behaviour/properties is induced by using different coformers, such as urea, saccharin, gentisic acid, salicylic acid, glutaric acid, sorbic acid, 1-hydroxy-2-naphthoic acid, oxalic acid, maleic acid and nicotinamide. The solubility of each coformer in the dissolution medium of phosphate-buffered saline (pH 7.4 at 25 °C), could determine the dissolving rate behaviour of the produced cocrystals. Consequently, the low-soluble coformers generate TPL cocrystals with a slow-dissolving rate, while the use of highly-soluble coformers produces faster-dissolving TPL cocrystals. Albeit the SEA process operating temperature influences the mean cocrystal particle size, this technique shows a high potential as an effective cocrystal screening tool.

  • 42.
    Dudenko, D.V.
    et al.
    Cardiff University.
    Williams, P.A.
    Cardiff University.
    Hughes, C.E.
    Cardiff University.
    Antzutkin, Oleg
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Industriell miljö- och processteknik.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Brown, S.P.
    University of Warwick.
    Harris, K.D.M.
    Cardiff University.
    Exploiting the synergy of powder x-ray diffraction and solid-state NMR spectroscopy in structure determination of organic molecular solids2013Ingår i: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 117, nr 23, s. 12258-12265Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report a strategy for structure determination of organic materials in which complete solid-state nuclear magnetic resonance (NMR) spectral data is utilized within the context of structure determination from powder X-ray diffraction (XRD) data. Following determination of the crystal structure from powder XRD data, first-principles density functional theory-based techniques within the GIPAW approach are exploited to calculate the solid-state NMR data for the structure, followed by careful scrutiny of the agreement with experimental solid-state NMR data. The successful application of this approach is demonstrated by structure determination of the 1:1 cocrystal of indomethacin and nicotinamide. The 1H and 13C chemical shifts calculated for the crystal structure determined from the powder XRD data are in excellent agreement with those measured experimentally, notably including the two-dimensional correlation of 1H and 13C chemical shifts for directly bonded 13C-1H moieties. The key feature of this combined approach is that the quality of the structure determined is assessed both against experimental powder XRD data and against experimental solid-state NMR data, thus providing a very robust validation of the veracity of the structure

  • 43.
    Gavini, Elisabetta
    et al.
    Department of Chemistry and Pharmacy, University of Sassari.
    Rassu, Giovanna
    Department of Chemistry and Pharmacy, University of Sassari.
    Ferraro, Luca
    Department of Experimental and Clinical Medicine, Pharmacology Section, University of Ferrara.
    Beggiato, Sarah
    Department of Experimental and Clinical Medicine, Pharmacology Section, University of Ferrara.
    Alhalaweh, Amjad
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Marchetti, Nichola
    Department of Chemistry, University of Ferrara.
    Bandiera, Pasquale
    Department of Biomedical Sciences, University of Sassari.
    Giunchedi, Paolo
    Department of Chemistry and Pharmacy, University of Sassari.
    Dalpiaz, Alessandro
    Department of Pharmaceutical Sciences, University of Ferrara.
    Influence of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting2013Ingår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 83, nr 2, s. 174-183Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to investigate the effect of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting. Mucoadhesive powder formulations consisted of antimigraine drug, zolmitriptan, and chitosans (various molecular weights and types) or hydroxypropyl methylcellulose (HPMC). Their suitability for nasal administration was evaluated by in-vitro and ex-vivo mucoadhesion and permeation tests. The formulations based on chitosan glutamate (CG) or HPMC were tested in-vivo because they showed good mucoadhesive properties and altered the permeation rate of the drug. The in-vivo results from intravenous infusion and nasal aqueous suspension of the drug or nasal particulate powders were compared. The plasmatic AUC values obtained within 8 h following intravenous administration appeared about three times higher than those obtained by nasal administration, independent of the formulations. Zolmitriptan concentrations in the cerebrospinal fluid obtained from nasal and intravenous administrations were respectively 30 and 90 times lower than the concentrations of the drug in the blood. Thus, nasal administration potentiated the central zolmitriptan activity allowing a reduction of the drug peripheral levels, with respect to the intravenous administration. Among nasally administered formulations, CG microparticles showed the highest efficacy in promoting the central uptake of zolmitriptan within 1 h.

  • 44.
    Alhalaweh, Amjad
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Kaialy, Waseem
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Buckton, Graham
    Department of Pharmaceutics, School of Pharmacy, University College London.
    Gill, Hardyal
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Nokhodchi, Ali
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Theophylline cocrystals prepared by spray drying: physicochemical properties and aerosolization performance2013Ingår i: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 14, nr 1, s. 265-276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this work was to characterize theophylline (THF) cocrystals prepared by spray drying in terms of the physicochemical properties and inhalation performance when aerosolized from a dry powder inhaler. Cocrystals of theophylline with urea (THF-URE), saccharin (THF-SAC) and nicotinamide (THF-NIC) were prepared by spray drying. Milled THF and THF-SAC cocrystals were also used for comparison. The physical purity, particle size, particle morphology and surface energy of the materials were determined. The in vitro aerosol performance of the spray-dried cocrystals, drug-alone and a drug-carrier aerosol, was assessed. The spray-dried particles had different size distributions, morphologies and surface energies. The milled samples had higher surface energy than those prepared by spray drying. Good agreement was observed between multi-stage liquid impinger and next-generation impactor in terms of assessing spray-dried THF particles. The fine particle fractions of both formulations were similar for THF, but drug-alone formulations outperformed drug-carrier formulations for the THF cocrystals. The aerosolization performance of different THF cocrystals was within the following rank order as obtained from both drug-alone and drug-carrier formulations: THF-NIC > THF-URE > THF-SAC. It was proposed that micromeritic properties dominate over particle surface energy in terms of determining the aerosol performance of THF cocrystals. Spray drying could be a potential technique for preparing cocrystals with modified physical properties.

  • 45.
    Ali, Hassan
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Alhalaweh, Amjad
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin2013Ingår i: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 39, nr 5, s. 625-634Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context:Identification of optimal solid form of an active pharmaceutical ingredient and form control are very important in drug development. Thus, the structural information of these forms and in-depth insight on the modes of molecular interactions are necessary, and vibrational spectroscopic methods are well suited for this purpose.Objective:In-depth structural analysis of different solid forms of indomethacin (IND) using Raman and infrared (IR) spectroscopy is the objective. We have investigated the modes of molecular interactions in polymorphs (α and γ), amorphous and discovered cocrystals of IND with nicotinamide (NIC) and trans-cinnamic acid (CIN) coformers.Materials and methods: The solid forms of IND have been prepared; their purity has been verified by differential scanning calorimetry and powder X-ray diffractometry and then studied in the solid-state by Raman and IR spectroscopy. The modes of the interactions were closely investigated from the vibrational data.Results: The key vibrational features of IND solid forms have been specified. The IR (C=O) band at 1713 cm−1 attributed to cyclic acid dimer of γ IND has disappeared in IND–NIC/CIN whilst retained in IND–SAC cocrystal.Discussion:IND cocrystallizes in different conformations and crystal lattices with different coformers. The cyclic acid dimer of IND has been kept on its cocrystallization with saccharin and it could have been broken with NIC and CIN.Conclusions: The complementary nature of Raman and IR spectroscopy allowed unambiguous investigation of the chemical composition of pharmaceutical materials which is of particular importance in the absence of detailed structural information, as in the case of IND–NIC and IND–CIN.

  • 46.
    Maruyoshi, K.
    et al.
    University of Warwick.
    Iuga, D.
    University of Warwick.
    Antzutkin, Oleg
    Luleå tekniska universitet, Institutionen för samhällsbyggnad och naturresurser, Industriell miljö- och processteknik.
    Alhalaweh, Amjad
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Brown, S.P.
    University of Warwick.
    Identifying the intermolecular hydrogen-bonding supramolecular synthons in an indomethacin-nicotinamide cocrystal by solid-state NMR2012Ingår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, nr 88, s. 10844-10846Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two-dimensional 1H double-quantum and 14N- 1H & 1H- 13C heteronuclear magic-angle spinning (MAS) NMR spectra recorded at natural isotopic abundance identify specific intermolecular COOH⋯N arom and CH arom⋯OC hydrogen-bonding interactions in the solid-state structure of an indomethacin-nicotinamide cocrystal, thus additionally proving cocrystal formation.

  • 47.
    Kaialy, Waseem
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Alhalaweh, Amjad
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Nokhodchi, Ali
    Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent.
    Influence of lactose carrier particle size on the aerosol performance of budesonide from a dry powder inhaler2012Ingår i: Powder Technology, ISSN 0032-5910, E-ISSN 1873-328X, Vol. 227, s. 74-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this study was to evaluate the effect of carrier particle size on properties of dry powder and its effect on dry powder inhaler (DPI) performance. Commercial α-lactose-monohydrate, a commonly used carrier in DPI formulations, was carefully sieved to obtain different lactose size fractions, namely Lac A (90–125 μm), Lac B (63–90 μm), Lac C (45–63 μm), Lac D (20–45 μm), and Lac E (< 20 μm). The lactose samples were analysed in terms of size, shape, solid state, density, and flowability. Lactose particles were blended with budesonide (< 5 μm) powder to generate five different formulations. These formulations were then evaluated in terms of budesonide-lactose adhesion properties, drug content homogeneity, and in vitro aerosolisation performance. The results demonstrated that lactose samples with smaller particle volume mean diameter have higher amorphous lactose content, higher true density (linear, r2 = 0.9932), higher surface smoothness (linear, r2 = 0.8752), smaller angularity (linear, r2 = 0.921), smaller bulk density, higher porosity (linear, r2 = 0.914), poorer flowability, and higher specific surface area. In general, the smaller the lactose particles the smaller are the budesonide-lactose adhesion properties. Budesonide formulated with smaller lactose particles exhibited smaller aerodynamic diameter and higher amounts of budesonide were delivered to lower stages of the impactor indicating improved DPI aerosolisation performance. However, the use of lactose particles with smaller volume mean diameter had a detrimental effect on budesonide content homogeneity and caused an increase in the amounts of budesonide deposited on oropharyngeal region. Therefore, particle size of the lactose within dry powder inhaler formulations should be selected carefully. Accordingly, higher drug aerosolisation efficiency of lactose particles with smaller size may have to be balanced due to considerations of other disadvantages including poorer flowability, reduced formulation stability, higher potential side effects, and higher dose variability.

  • 48.
    Alhalaweh, Amjad
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    George, Sumod
    Basavoju, Srinivas
    Childs, S.L.
    Renovo Research, Atlanta, GA.
    Rizvi, S.A.A.
    College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Pharmaceutical cocrystals of nitrofurantoin: Screening, characterization and crystal structure analysis2012Ingår i: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 14, nr 15, s. 5078-5088Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to screen and prepare cocrystals of the poorly soluble drug nitrofurantoin (NTF) with the aim of increasing its solubility. Screening for cocrystals of NTF using 47 coformers was performed by high-throughput (HT) screening using liquid assisted grinding (LAG) methods. Raman spectroscopy and powder X-ray diffraction (PXRD) were used as the primary analytical tools to identify the new crystalline solid forms. Manual LAG and reaction crystallization (RC) experiments were carried out to confirm and scale-up the hits. Seven hits were confirmed to be cocrystals. The cocrystals were characterized by PXRD, Raman and IR spectroscopy, thermal analysis (DSC and TGA) and liquid-state NMR or elemental analysis. The solution stability of the scaled-up cocrystals in water was tested by slurrying the cocrystals at 25 °C for one week. NTF forms cocrystals with a 1:1 stoichiometric ratio with urea (1), 4-hydroxybenzoic acid (2), nicotinamide (3), citric acid (4), l-proline (5) and vanillic acid (6). In addition, NTF forms a 1:2 cocrystal with vanillin (7). All but one of the NTF cocrystals transformed (dissociated) in water, resulting in NTF hydrate crystalline material or NTF hydrate plus the coformer, which indicates that the transforming cocrystals have a higher solubility than the NTF hydrate under these conditions. The crystal structures of 1:1 NTF-citric acid (4) and 1:2 NTF-vanillin (7) were solved by single-crystal X-ray diffraction. The crystal structures of these two cocrystals were analyzed in terms of their supramolecular synthons.

  • 49.
    Basavoju, Srinivas
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Boström, Dan
    Energy Technology and Thermal Process Chemistry, Umeå University.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Pharmaceutical salts of fluoroquinolone antibacterial drugs with acesulfame sweetener2012Ingår i: Molecular Crystals and Liquid Crystals, ISSN 1542-1406, E-ISSN 1563-5287, Vol. 562, nr 1, s. 254-264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Novel organic salts of norfloxacin and ciprofloxacin with artificial sweeteners such as saccharin and acesulfame were prepared. The two salts 1 and 2 were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Finally, the crystal structures were solved by single crystal X-ray diffraction data and the structures were analyzed in terms of supramolecular synthons. In norfloxacin acesulfamate 1, two norfloxacin cations and two acesulfame anions form an eight membered cyclic tetramer supramolecular synthon. The salt, ciprofloxacin acesulfamate 2, has a similar structure as salt 1. This study contributes the importance of crystal engineering and supramolecular chemistry to the pharmaceutical applications in terms of interactions and structural correlations in the design of new solid phases. Supplemental materials are available for this article. Go to the publisher's online edition of Molecular Crystals and Liquid Crystals to view the free supplemental file

  • 50.
    Alhalaweh, Amjad
    et al.
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Roy, Lilly
    Department of Pharmaceutical Sciences, University of Michigan.
    Rodriguez-Hornedo, Nair
    Department of Pharmaceutical Sciences, University of Michigan.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    pH-dependent solubility of indomethacin-saccharin and carbamazepine-saccharin cocrystals in aqueous media2012Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, nr 9, s. 2605-2612Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.

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