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1.
Drug Discov Today ; 26(10): 2329-2349, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34265460

RESUMO

The barrier function of skin and the non-optimal physicochemical properties of drugs present challenges to the skin penetration of many drugs, thus motivating the development of novel drug delivery systems. Recently, nanocrystal-based formulations have been investigated for topical drug delivery and have demonstrated improved skin penetration. This review highlights barriers in skin penetration, current techniques to improve topical delivery and application of nanocrystals in conquering obstacles for topical delivery. Nanocrystals can improve delivery through the skin by mechanisms including the creation of a higher concentration gradient across skin resulting in increased passive diffusion, hair follicle targeting, formation of diffusional corona, and adhesion to skin. The recent research would be of interest for formulation scientists seeking to develop products involving molecules that are 'difficult-to-deliver' topically.

2.
Int J Pharm ; 607: 120958, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34332060

RESUMO

Supersaturating drug delivery systems (SDDS) enhance the oral absorption of poorly water-soluble drugs by achieving a supersaturated state in the gastrointestinal tract. The maintenance of a supersaturated state is decided by the complex interplay among inherent properties of drug, excipients and physiological conditions of gastrointestinal tract. The biopharmaceutical advantage through SDDS can be mechanistically investigated by coupling biopredictive dissolution testing with physiologically based absorption modeling (PBAM). However, the development of biopredictive dissolution methods possess challenges due to concurrent dissolution, supersaturation, precipitation, and possible redissolution of precipitates during gastrointestinal transit of SDDS. In this comprehensive review, our effort is to critically assess the current state-of-knowledge and provide future directions for PBAM of SDDS. The review outlines various methods used to retrieve physiologically relevant values for input parameters like solubility, dissolution, precipitation, lipid-digestion and permeability of SDDS. SDDS-specific parameterization includes solubility values corresponding to apparent physical form, dissolution in physiologically relevant volumes with biorelevant media, and transfer experiments to incorporate precipitation kinetics. Interestingly, the lack of experimental permeability values and modification of absorption flux through SDDS possess the additional challenge for its PBAM. Supersaturation triggered permeability modifications are reported to fit the observed plasma concentration-time profile. Hence, the experimental insights on good fitting with modified permeability can be potential area of future research for the development of in vitro methods to reliably predict oral absorption of SDDS.


Assuntos
Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas , Administração Oral , Excipientes , Permeabilidade , Solubilidade
3.
AAPS PharmSciTech ; 22(5): 201, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34231193

RESUMO

Particle engineering of excipients, at sub-particulate level using co-processing, can provide high functionality excipients. NanoCrySP technology has been recently explored as a novel approach for the generation of nanocrystalline solid dispersion of poorly soluble drugs, using spray drying process. The purpose of the present study was to generate co-processed mannitol and sorbitol (SD-CSM) using NanoCrySP technology having similar composition to commercial co-processed excipient (Compressol® SM, CP). The characterization of excipients was performed to evaluate their various physicomechanical properties. The sub-micron crystallite size of sorbitol in the matrix of mannitol was determined using the Williamson-Hall equation and Halder-Wagner equation. The reduction in crystallite size of sorbitol and mannitol, lower melting point, and lower heat of fusion of SD-CSM could be responsible for excellent compactibility, better tabletability, and comparable compressibility with respect to CP. This was confirmed by the compressibility-tabletability-compactibility (CTC) profile and Heckel plot analysis. Overall, SD-CSM generated using NanoCrySP technology improved functionalities of excipients over CP and would be useful for direct compression application.


Assuntos
Composição de Medicamentos/métodos , Manitol/química , Nanotecnologia , Sorbitol/química , Força Compressiva , Cristalização , Excipientes/química , Tamanho da Partícula , Porosidade , Comprimidos/química , Resistência à Tração , Molhabilidade
4.
Mol Pharm ; 18(8): 2835-2866, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34041914

RESUMO

In the pharmaceutical industry, poorly water-soluble drugs require enabling technologies to increase apparent solubility in the biological environment. Amorphous solid dispersion (ASD) has emerged as an attractive strategy that has been used to market more than 20 oral pharmaceutical products. The amorphous form is inherently unstable and exhibits phase separation and crystallization during shelf life storage. Polymers stabilize the amorphous drug by antiplasticization, reducing molecular mobility, reducing chemical potential of drug, and increasing glass transition temperature in ASD. Here, drug-polymer miscibility is an important contributor to the physical stability of ASDs. The current Review discusses the basics of drug-polymer interactions with the major focus on the methods for the evaluation of solubility and miscibility of the drug in the polymer. Methods for the evaluation of drug-polymer solubility and miscibility have been classified as thermal, spectroscopic, microscopic, solid-liquid equilibrium-based, rheological, and computational methods. Thermal methods have been commonly used to determine the solubility of the drug in the polymer, while other methods provide qualitative information about drug-polymer miscibility. Despite advancements, the majority of these methods are still inadequate to provide the value of drug-polymer miscibility at room temperature. There is still a need for methods that can accurately determine drug-polymer miscibility at pharmaceutically relevant temperatures.

5.
Mol Pharm ; 18(6): 2334-2348, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34003656

RESUMO

Numerous amorphous solid dispersion (ASD) formulations of celecoxib (CEL) have been attempted for enhancing the solubility, dissolution rate, and in vivo pharmacokinetics via high drug loading, polymer combination, or by surfactant addition. However, physical stability for long-term shelf life and desired in vivo pharmacokinetics remains elusive. Therefore, newer formulation strategies are always warranted to address poor aqueous solubility and oral bioavailability with extended shelf life. The present investigation elaborates a combined strategy of amorphization and salt formation for CEL, providing the benefits of enhanced solubility, dissolution rate, in vivo pharmacokinetics, and physical stability. We generated amorphous salts solid dispersion (ASSD) formulations of CEL via an in situ acid-base reaction involving counterions (Na+ and K+) and a polymer (Soluplus) using the spray-drying technique. The generated CEL-Na and CEL-K salts were homogeneously and molecularly dispersed in the matrix of Soluplus polymer. The characterization of generated ASSDs by differential scanning calorimetry revealed a much higher glass-transition temperature (Tg) than the pure amorphous CEL, confirming the salt formation of CEL in solid dispersions. The micro-Raman and proton nuclear magnetic resonance spectroscopy further confirmed the formation of salt at the -S═O position in the CEL molecules. CEL-Na-Soluplus ASSD exhibited a synergistic enhancement in the aqueous solubility (332.82-fold) and in vivo pharmacokinetics (9.83-fold enhancement in the blood plasma concentration) than the crystalline CEL. Furthermore, ASSD formulations were physically stable for nearly 1 year (352 days) in long-term stability studies at ambient conditions. Hence, we concluded that the ASSD is a promising strategy for CEL in improving the physicochemical properties and biopharmaceutical performance.

6.
Expert Opin Drug Deliv ; 18(7): 907-928, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33412936

RESUMO

INTRODUCTION: Polymers have various applications such as binder, film coating agent, stabilizer, drug release modification, and as primary packaging materials. Recently, they have been explored in co-processing technique to improve the functionality of small molecule excipients (SMEs). Co-processing is a concept wherein two or more excipients interact at sub-particle level to provide synergy in functionality and minimize drawbacks of individual excipients. AREA COVERED: The present review highlights the application of co-processing to improve the functionality of SMEs using polymers; physicochemical and mechanical properties of polymers for co-processing; advantages of co-processed excipients for different applications; functionality enhancement of co-processed excipients; novel concepts/methods for co-processing; mechanistic insights on co-processing and commercial products available in the market. EXPERT OPINION: Most of the SMEs do not possess optimal multifunctional properties like flow, compressibility, compactibility, and disintegration ability, required to compensate for poorly compactable drugs. Some of these drawbacks can be overcome by co-processing of SMEs with polymers. For example, co-processing of a brittle SME and plastic material (polymer) can provide a synergistic effect and result in the generation of single entity multi-functional excipient. Besides, novel co-processed excipients generated using combinations of SMEs and polymers can also generate intellectual property rights.


Assuntos
Excipientes , Polímeros , Liberação Controlada de Fármacos , Comprimidos
7.
Drug Deliv Transl Res ; 11(3): 966-983, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32588281

RESUMO

Nanocrystals can enhance skin penetration of drug by increased saturation solubility, dissolution rate and adhesion on the skin. Apremilast is 'difficult-to-deliver' in viable layers (epidermis, dermis) and stratum corneum (SC) owing to its poor aqueous solubility and modest lipophilicity, respectively. Apremilast is currently available as oral tablet formulation for the indication of psoriasis but its effectiveness is limited by systemic side effects. Therefore, the present study aimed to develop novel nanocrystal-based formulations of apremilast for improved topical delivery. Nanosuspension was prepared using wet media milling and exhibited a mean particle size of 200 nm. The saturation solubility of nanocrystals was improved by 2-fold than micronized apremilast and showed significant advantage during dissolution study. Nanosuspension and micronized apremilast was incorporated into gel and cream and characterized for rheological properties. Skin permeation and ex vivo dermatokinetic study of topical formulations were performed on pig ear skin at a dose of 1% w/w using Franz diffusion cells. Skin permeation studies indicated that non-detectable amount of apremilast permeated through pig ear skin during exposure of formulations. Nanosuspension showed 2.6- and 3.2-fold drug penetration in SC and viable layers, respectively, over microsuspension. Nanogel showed 2.7- and 2.4-fold drug penetration in SC and viable layers, respectively, over microgel. Nanocream showed 1.2- and 2.8-fold drug penetration in SC and viable layers, respectively, over microcream. Thus, nanocrystal-based formulations of apremilast aid in selective delivery into viable layers by crossing the SC barrier. This is of paramount importance in enhancing therapeutic effectiveness utilizing localized delivery and provides an alternative delivery approach for the treatment of psoriasis. Graphical abstract.

8.
J Pharm Sci ; 110(4): 1470-1479, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33333143

RESUMO

In present work, a correlationship among quantitative drug-polymer miscibility, molecular relaxation and phase behavior of the dipyridamole (DPD) amorphous solid dispersions (ASDs), prepared with co-povidone (CP), hydroxypropyl methylcellulose phthalate (HPMC P) and hydroxypropyl methylcellulose acetate succinate (HPMC AS) has been investigated. Miscibility predicted using melting point depression approach for DPD with CP, HPMC P and HPMC AS at 25 °C was 0.93% w/w, 0.55% w/w and 0.40% w/w, respectively. Stretched relaxation time (τß) for DPD ASDs, measured using modulated differential scanning calorimetry (MDSC) at common degree of undercooling, was in the order of DPD- CP > DPD-HPMC P > DPD-HPMC AS ASDs. Phase behavior of 12 months aged (25 ± 5 °C and 0% RH) spray dried 60% w/w ASDs was tracked using MDSC. Initial ASD samples had homogeneous phase revealed by single glass transition temperature (Tg) in the MDSC. MDSC study of aged ASDs revealed single-phase DPD-CP ASD, amorphous-amorphous and amorphous-crystalline phase separated DPD-HPMC P and DPD-HPMC AS ASDs, respectively. The results were supported by X-ray micro computed tomography and confocal laser scanning microscopy studies. This study demonstrated a profound influence of drug-polymer miscibility on molecular mobility and phase behavior of ASDs. This knowledge can help in designing "physical stable" ASDs.


Assuntos
Preparações Farmacêuticas , Polímeros , Varredura Diferencial de Calorimetria , Dipiridamol , Solubilidade , Microtomografia por Raio-X
9.
Int J Pharm ; 585: 119489, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32522504

RESUMO

Spray drying is an industrially viable technique that can be used for modulation of the physical form of Active Pharmaceutical Ingredients (API), which is governed by inherent crystallization tendency and processing parameters during spray drying. In the current study, we investigated the role of solvent in differential phase behavior of celecoxib, a poor crystallizer, during spray drying and unveiled the underlying mechanisms. 1% w/v solutions of celecoxib in three different compositions of methanol (M)-water (W) solvent system were spray dried using a laboratory spray dryer. The proportions were 0, 5 and 10% v/v of water in methanol (MW0, MW5, and MW10, respectively). Percentage crystallinity of the spray dried products were evaluated using modulated differential scanning calorimetry and was in the order MW10 > MW5 > MW0 (i.e. 18.52% > 8.13% > 0%). Solution-state and solid-state crystallization events responsible for the experimental observations were probed using microscopy, Raman spectroscopy, and non-isothermal crystallization studies. An intermediate amorphous phase was generated for the studied samples, which underwent crystallization under the influence of chamber temperature for MW5 and MW10. Additionally, liquid-liquid phase separation (LLPS) at very high level of supersaturation led to relatively higher crystallinity for MW10. Insights from this work provide the basis for understanding of probable phase behavior of poor crystallizers during spray drying.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Celecoxib/síntese química , Solventes/síntese química , Secagem por Atomização , Anti-Inflamatórios não Esteroides/análise , Varredura Diferencial de Calorimetria/métodos , Celecoxib/análise , Solventes/análise , Análise Espectral Raman/métodos , Difração de Raios X/métodos
10.
Int J Pharm ; 586: 119555, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32562654

RESUMO

Intravenous (IV) route is preferred for rapid onset of action, avoiding first pass metabolism and achieving site specific delivery. Development of IV formulations for poorly water soluble drugs poses significant challenges. Formulation approaches like salt formation, co-solvents, surfactants and inclusion complexation using cyclodextrins are used for solubilisation. However, these approaches are not applicable universally and have limitations in extent of solubilisation, hypersensitivity, toxicity and application to only specific type of molecules. IV nanosuspension have been attracting attention as a viable strategy for development of IV formulations of poorly water-soluble drugs. Nanosuspension consists of nanocrystals of poorly water soluble drug suspended in aqueous media and stabilized using minimal concentration of stabilizers. Recent years have witnessed their potential in formulations for toxicological studies and clinical trials. However various challenges are associated with the translational development of IV nanosuspensions. Therefore, the objective of the current review is to provide a holistic view of formulation development and desired properties of IV nanosuspensions. It will also focus on advancements in characterization tools, manufacturing techniques and post-production processing. Challenges associated with translational development and regulatory aspects of IV nanosuspension will be addressed. Additionally, their role in preclinical evaluation and special applications like targeting will also be discussed with the help of case studies. The applications of IV nanosuspensions shall expand as their applications move from preclinical phase to commercialization.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Preparações Farmacêuticas/administração & dosagem , Administração Intravenosa , Animais , Química Farmacêutica , Humanos , Preparações Farmacêuticas/química , Solubilidade , Suspensões , Tecnologia Farmacêutica , Água/química
11.
Pharmaceutics ; 12(6)2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32545503

RESUMO

The present work aims to understand the crystallographic basis of the mechanical behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL Co) in comparison to its parent constituents, i.e., rivaroxaban (RIV) and malonic acid (MAL). The mechanical behavior was evaluated at the bulk level by performing "out of die" bulk compaction and at the particle level by nanoindentation. The tabletability order for the three solids was MAL < RIV < RIV-MAL Co. MAL demonstrated "lower" tabletability because of its lower plasticity, despite it having reasonably good bonding strength (BS). The absence of a slip plane and "intermediate" BS contributed to this behavior. The "intermediate" tabletability of RIV was primarily attributed to the differential surface topologies of the slip planes. The presence of a primary slip plane (0 1 1) with flat-layered topology can favor the plastic deformation of RIV, whereas the corrugated topology of secondary slip planes (1 0 ) could adversely affect the plasticity. In addition, the higher elastic recovery of RIV crystal also contributed to its tabletability. The significantly "higher" tabletability of RIV-MAL Co among the three molecular solids was the result of its higher plasticity and BS. Flat-layered topology slip across the (0 0 1) plane, the higher degree of intermolecular interactions, and the larger separation between adjacent crystallographic layers contributed to improved mechanical behavior of RIV-MAL Co. Interestingly, a particle level deformation parameter H/E (i.e., ratio of mechanical hardness H to elastic modulus E) was found to inversely correlate with a bulk level deformation parameter σ0 (i.e., tensile strength at zero porosity). The present study highlighted the role of cocrystal crystallographic properties in improving the tabletability of materials.

12.
J Pharm Sci ; 109(2): 1105-1114, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31705872

RESUMO

NanoCrySP™ is a novel spray-drying-based technology for the generation of nanocrystalline solid dispersions of active pharmaceutical ingredients embedded in the matrix of small molecule excipients. Active pharmaceutical ingredient first appears as an amorphous phase, which transforms to crystalline phase during its passage in the drying chamber. Mannitol acts as a crystallization inducer for the intermediate amorphous phase by primary heterogeneous nucleation. Heteronucleation is a surface-assisted phenomenon and surface characteristics of mannitol were hypothesized to play important role. This study investigates the role of surface characteristics of mannitol on crystallization kinetics of amorphous fenofibrate. Crystallization kinetics of amorphous fenofibrate was assessed on 2 surfaces of mannitol having different porosity, roughness, and polarity. Fenofibrate showed faster crystallization in the presence of rougher surface (tind < 1 min) compared with smooth surface (tind = 49.28 min). This was attributed to higher porosity (75%) and surface polarity (~1.25-fold) of rough surface as compared with smooth surface. Polar nature provided primitive sites for faster crystallization of amorphous fenofibrate. These findings can be utilized for generating crystalline solid dispersions using spray drying in the presence of mannitol. The crystalline solid dispersions can be used for the development of oral solid dosage forms.


Assuntos
Fenofibrato , Manitol , Cristalização , Excipientes , Solubilidade , Secagem por Atomização
13.
Drug Dev Res ; 81(1): 3-22, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31800139

RESUMO

Crystallization is an important and difficult to control unit operation in the pharmaceutical industry. Crystallization can control molecular (i.e., polymorphism) and particulate (i.e., particle size and crystal habit) properties of active pharmaceutical ingredient (API). Moreover, these molecular and particulate properties govern the manufacturability, stability, and biopharmaceutical performance of the API and drug product. Nucleation is a key step and primary heterogeneous nucleation is a common mode of nucleation during crystallization. Hence, it is important to understand the parameters affecting primary heterogeneous nucleation, to achieve desirable properties in crystalline APIs. Primary heterogeneous crystallization has usually been linked to the surface characteristics like topography and functionality of the heteronucleant. The review outlines recent findings in the primary heterogeneous crystallization with specific emphasis on its pharmaceutical applications including regulatory considerations. Molecular-level mechanisms governing heteronucleation and subsequent outcome in terms of molecular as well as particulate-level properties of API have also been discussed. Moreover, general guidance for the selection of heteronucleant has also been included. Heterogeneous crystallization is a promising tool for efficient crystallization of API having properties for optimal pharmaceutical performance.


Assuntos
Preparações Farmacêuticas/química , Cristalização , Estrutura Molecular , Tamanho da Partícula , Tecnologia Farmacêutica
14.
Mol Pharm ; 16(11): 4610-4620, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31573811

RESUMO

Cocrystallization studies were undertaken to improve the solubility of a highly water-insoluble drug, febuxostat (FXT), used in the treatment of gout and hyperuricemia. A liquid-assisted grinding (LAG) method was successfully employed, starting with the screening of various coformers for obtaining cocrystals. However, in this process, three eutectic systems with coformers (probenecid, adipic acid, and α-ketoglutaric acid) were formed. Affinities of the different functional groups to form a hydrogen bond and ΔpKa differences, leading to the eutectic formation, were discussed. The eutectic systems thus formed were further characterized and analyzed using a differential scanning calorimeter (DSC) and powder X-ray diffraction (PXRD). Binary thermal phase diagrams were plotted using different ratios of the systems to confirm the formation of eutectics, and pH-dependent solubility studies exhibited a significant decrease in the solubility in comparison to that of the drug for all three eutectic systems. The solubility of FXT reduced from 46.53 µg/mL (pH 5.63) to 46.03 µg/mL, 28.53 µg/mL, and 18.88 µg/mL; 770.58 µg/mL (pH 8.21) to 307.574 µg/mL, 116.63 µg/mL, 113.40 µg/mL; and from 13165.97 µg/mL (pH 10.13) to 1409.737 µg/mL, 854.51 µg/mL, and 1218.99 µg/mL for FXT-probenecid, FXT-adipic acid, and FXT-α-ketoglutaric acid eutectic systems, respectively. Furthermore, the microenvironmental pH studies were carried out to understand the effect of the microenvironment on the solubility of these eutectic systems. The contribution to solubility from lattice and nonlattice forces considering the microenvironment was also discussed.


Assuntos
Febuxostat/química , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Humanos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Difração de Pó/métodos , Pós/química , Solubilidade/efeitos dos fármacos , Difração de Raios X/métodos
15.
Drug Dev Ind Pharm ; 45(12): 1940-1948, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31625418

RESUMO

The present work aimed to investigate the impact of primary drying temperature on lyophilization process efficiency and product performance of lyophilized Ertapenam sodium (EPM). Phase behavior of EPM formulation (200 mg/mL) using differential scanning calorimetry (DSC) and freeze drying microscopy (FDM) showed Tg' at -28.3 °C (onset) and Tc at -25.0 °C (onset), respectively. The formulation was freeze dried at different product temperature (Tp) during primary drying, using (a) conservative cycle (CC) where the maximum Tp (-31.9 °C) Tg', and (c) AC02 where the maximum Tp (-21.0 °C) >Tc. The drying kinetics revealed that the sublimation rate was increased from 0.128 g/h/vial in CC to 0.159 and 0.182 g/h/vial in AC01 and AC02, respectively. This ultimately reduced the primary drying time of 208 min in CC to 145 min in AC01 and to 103 minutes in AC02. Morphological evaluation of cake using scanning electron microscopy (SEM) and texture analysis revealed that AC01 lead to induction of microcollapse, whereas AC02 resulted in collapsed cake. Furthermore, the microcollapsed formulations showed similar physicochemical stability to CC formulation, whereas collapsed cake showed significant degradation of EPM and increased degradation on stress stability. The study highlights that primary drying with microcollapse can be utilized to improve the process efficiency without compromising product quality of amorphous EPM.


Assuntos
Antibacterianos/química , Composição de Medicamentos/métodos , Ertapenem/química , Varredura Diferencial de Calorimetria , Dessecação/métodos , Estabilidade de Medicamentos , Excipientes/química , Liofilização/métodos , Microscopia/métodos , Temperatura
16.
Mol Pharm ; 16(10): 4139-4148, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31454247

RESUMO

In the present study, we have investigated the variability in physical properties of povidone K30 (PVP K30) and its impact on crystallization and drug-polymer miscibility of celecoxib-PVP K30 (CLB-PVP K30) amorphous solid dispersions (ASDs). CLB-PVP K30 ASDs were prepared using nine batches of PVP K30, in situ on glass slides by quench-cooling using the hot and cold stage of a microscope. Crystallization of the ASDs stored at 40 ± 2 °C/75 ± 5% relative humidity was captured using polarized light microscopy for up to 24 h and quantified using mean pixel counts of images. The quantitative drug-polymer miscibility of nine CLB-PVP K30 systems was determined using melting point depression. Pearson's correlation analysis was used to find the correlation between (i) % crystallization with drug-polymer miscibility and physical properties and (ii) drug-polymer miscibility and physical properties, of PVP K30. The % crystallization was significantly variable (p < 0.05) among the nine CLB-PVP K30 ASDs. The nine PVP K30 batches exhibited significant variability (p < 0.05) from batch to batch and/or source to source in physical properties. The % crystallization showed correlation to particle size distribution (PSD) (weak positive), glass transition (Tg) (weak positive), drug-polymer miscibility (moderate negative), true density, and porosity (moderate positive) and hygroscopicity (strong positive). Miscibility showed correlation between Tg (weak positive), hygroscopicity (weak negative), PSD (moderate negative), and true density and porosity (strong negative). The study suggests PSD, hygroscopicity, true density, and porosity of PVP K30 as the functionality related characteristics for its intended functionality of physical stability when it is used as a stabilizer in ASDs.


Assuntos
Celecoxib/química , Estabilidade de Medicamentos , Polímeros/química , Povidona/química , Molhabilidade , Cristalização , Estrutura Molecular , Transição de Fase , Solubilidade , Termodinâmica
17.
Mol Pharm ; 16(7): 2980-2991, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31244222

RESUMO

The present study aims to investigate the molecular basis of water sorption behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL). It was hypothesized, that the amount of water sorbed by a crystalline solid is governed by the surface molecular environment of different crystal facets and their relative abundance to crystal surface. Water sorption behavior was measured using a dynamic vapor sorption analyzer. The surface molecular environment of different crystal facets and their relative contribution were determined using single crystal structure evaluation and face indexation analysis, respectively. The surface area-normalized water sorption for rivaroxaban (RIV), malonic acid (MAL), and RIV-MAL at 90% RH/25 °C was 0.28, 92.6, and 11.1% w/w, respectively. The crystal surface of MAL had a larger contribution (58.7%) of hydrophilic (Hphi) functional groups and showed the "highest" water sorption (92.6% w/w). On the contrary, RIV had a larger surface contribution (65.2%) of hydrophobic (Hpho) functional groups, and the smaller contribution (34.8%) of Hphi+Hpho groups exhibited the "lowest" water sorption (0.28% w/w). The "intermediate" water sorption (11.1% w/w) by RIV-MAL, as compared to RIV, was ascribed to the increased surface contribution of Hphi+Hpho groups (from 34.8 to 42.1%) and reduced hydrophobic surface contribution (from 65.2 to 57.9%). However, the significantly higher water gained (∼39-fold) by the cocrystal as compared to RIV, despite the nominal change in the surface contributions, was further attributed to the relatively stronger hydrogen bonding interactions between the surface-exposed carboxyl groups and water molecules. The study highlights that the amount of water sorbed by the cocrystal is governed by the surface molecular environment and additionally by the strength of hydrogen bonding. This investigation has implications on designing materials with a desired moisture-sorption property.


Assuntos
Cristalização , Malonatos/química , Rivaroxabana/química , Água/química , Molhabilidade , Varredura Diferencial de Calorimetria , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície , Difração de Raios X
18.
Mol Pharm ; 16(1): 151-164, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30482019

RESUMO

Solubility advantage of thermodynamically highly unstable cocrystals, which undergo solution-mediated phase transformation (SMPT) in less than 1 min, does not translate to enhanced dissolution. The present study was aimed to understand the impact of polymeric additives on dissolution of thermodynamically highly unstable cocrystal with specific emphasis on influence of drug-polymer interactions. Exemestane-maleic acid was selected as a model cocrystal with SMPT time of <30 s and eutectic constant ( Keu) of 75475. Hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP) were selected as polymers for a dissolution study based on measurement of induction time using precipitation study. In the presence of 0.2% w/v of HPC, the cocrystal showed significantly higher drug release (∼3-fold) as compared with the cocrystal in the absence of predissolved polymers. Differential dissolution profiles of the cocrystal were observed with each polymer and the order of increasing dissolution rate was found to be HPC ≈ HPMCAS > PVP. The molecular basis of the differential dissolution performance was investigated using infrared spectroscopy, solution-state nuclear magnetic resonance spectroscopy, and nuclear Overhauser effect spectroscopy (NOESY). The polymers with stronger interactions with drug in the cocrystal (HPMCAS and HPC) displayed higher dissolution rate as compared with that of no intermolecular interaction (PVP). The study also highlighted that, despite no influence of the polymers on the cocrystal SMPT, dissolution enhancement was achieved. This was attributed to small-sized drug crystals (1-3 µm) generated from the supersaturation-mediated crystallization and improved solvation due to drug-polymer interactions. These findings have implications on development of drug products using thermodynamically unstable cocrystals.


Assuntos
Polímeros/química , Androstadienos/química , Celulose/análogos & derivados , Celulose/química , Cromatografia Líquida de Alta Pressão , Cristalização , Espectroscopia de Ressonância Magnética , Metilcelulose/análogos & derivados , Metilcelulose/química , Espectrofotometria Infravermelho , Termodinâmica
19.
J Pharm Sci ; 108(3): 1195-1202, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30352215

RESUMO

The purpose of this study was to investigate the phase behavior of cyclophosphamide (CPA) during various stages of lyophilization, with special emphasis on obtaining crystalline CPA monohydrate (CPA-MH) in the lyophilized product. Subambient differential scanning calorimetry and low-temperature X-ray diffractometry (LTXRD) were used to study the phase behavior of CPA solution (3.7% w/v). In situ lyophilization in LTXRD chamber was used to monitor the phase transitions occurring during the drying stages. Finally, the implications of these findings were confirmed by freeze-drying the aqueous solution in a laboratory-scale freeze-dryer. The results suggested that CPA remains amorphous during freeze concentration, with a Tg' of -50°C. However, its crystallization as CPA-MH can be induced by annealing the frozen solution between -5°C and -10°C. In situ lyophilization in LTXRD showed that the CPA-MH crystallized during annealing, rapidly dehydrated during primary drying, thereby causing structural collapse. The dehydration of CPA-MH can be prevented by lowering the escaping tendency of water molecules from the crystal lattice of CPA-MH by maintaining the chamber pressure to 300, 400, or 500 mTorr. This study highlights the relationship of process parameters used during lyophilization with the solid form of lyophilized CPA.


Assuntos
Ciclofosfamida/química , Composição de Medicamentos/métodos , Liofilização , Transição de Fase , Varredura Diferencial de Calorimetria , Temperatura Baixa , Cristalização , Estabilidade de Medicamentos , Água/química , Difração de Raios X
20.
Eur J Pharm Sci ; 128: 240-249, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30553062

RESUMO

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in females as per the global cancer project (GLOBOCAN 2018) estimates of breast cancer incidence and mortality produced by the International Agency for Research on Cancer (IARC). In 2018, there will be 2,088,849 new cases of breast cancer and 626,679 cases of deaths due to breast cancer in 5 regions (Americas, Africa, Europe, Asia and Oceania) at 20 sites of the world. Epidemiologic studies on diet and cancer have guided the search for some nutraceuticals acting as anti-cancer agents. Hesperetin (HRN), the aglycone of hesperidin, a glycoside found in citrus fruits, has been reported to have anti-cancer effects by apoptosis induction and inhibition of cell proliferation in cancer cells. However, poor solubility of HRN has limited its absorption while deviating from its therapeutic benefit. The present study aimed to develop nanocrystalline solid dispersions (NSD) of HRN and evaluating the oral bioavailability in rats. The study also evaluated the efficacy of NSDs against the carcinogenic activity of DMBA in female rats. NSDs were optimized using design of experiments (DoE) and multivariate analysis (MVA) tools. The optimized NSD formulation showed an average particle size (Zavg) of 558.2 ±â€¯68.1 nm and ~70% release in 30 min. The in vivo pharmacokinetic study also construed remarkable improvement (3.3 and 2.1-fold increase in Cmax and AUC0-∞) in rate and extent of absorption and 4-fold reduction in Tmax by the optimized NSD formulation. In vivo chemoprevention study construed superior efficacy of the NSD formulation by reducing the tumor burden, delaying the onset of tumors and reducing the tumor weight and volume in DMBA-induced breast cancer rats. In conclusion, we present a simple NSD formulation of HRN with enhanced bioavailability and superior chemopreventive efficacy.


Assuntos
Antracenos/toxicidade , Hesperidina/uso terapêutico , Neoplasias Mamárias Animais/induzido quimicamente , Neoplasias Mamárias Experimentais/prevenção & controle , Nanopartículas , Piperidinas/toxicidade , Animais , Feminino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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