In Vitro Characterization of a Novel Polymeric System for Preparation of Amorphous Solid Drug Dispersions

Preparation of amorphous solid dispersions using polymers is a commonly used formulation strategy for enhancing the solubility of poorly water-soluble drugs. However, often a single polymer may not bring about a significant enhancement in solubility or amorphous stability of a poorly water-soluble drug. This study describes application of a unique and novel binary polymeric blend in preparation of solid dispersions. The objective of this study was to investigate amorphous solid dispersions of glipizide, a BCS class II model drug, in a binary polymeric system of polyvinyl acetate phthalate (PVAP) and hypromellose (hydroxypropyl methylcellulose, HPMC). The solid dispersions were prepared using two different solvent methods: rotary evaporation (rotavap) and fluid bed drug layering on sugar spheres. The performance and physical stability of the dispersions were evaluated with non-sink dissolution testing, powder X-ray diffraction (PXRD), and modulated differential scanning calorimetry (mDSC). PXRD analysis demonstrated an amorphous state for glipizide, and mDSC showed no evidence of phase separation. Non-sink dissolution testing in pH 7.5 phosphate buffer indicated more than twofold increase in apparent solubility of the drug with PVAP–HPMC system. The glipizide solid dispersions demonstrated a high glass transition temperature (T _g) and acceptable chemical and physical stability during the stability period irrespective of the manufacturing process. In conclusion, the polymeric blend of PVAP–HPMC offers a unique formulation approach for developing amorphous solid dispersions with the flexibility towards the use of these polymers in different ratios and combined quantities depending on drug properties.     

Amorphous Stabilization and Dissolution Enhancement of Amorphous Ternary Solid Dispersions: Combination of Polymers Showing Drug–Polymer Interaction for Synergistic Effects

The purpose of this study was to understand the combined effect of two polymers showing drug–polymer interactions on amorphous stabilization and dissolution enhancement of indomethacin (IND) in amorphous ternary solid dispersions. The mechanism responsible for the enhanced stability and dissolution of IND in amorphous ternary systems was studied by exploring the miscibility and intermolecular interactions between IND and polymers through thermal and spectroscopic analysis. Eudragit E100 and PVP K90 at low concentrations (2.5%–40%, w/w) were used to prepare amorphous binary and ternary solid dispersions by solvent evaporation. Stability results showed that amorphous ternary solid dispersions have better stability compared with amorphous binary solid dispersions. The dissolution of IND from the ternary dispersion was substantially higher than the binary dispersions as well as amorphous drug. Melting point depression of physical mixtures reveals that the drug was miscible in both the polymers; however, greater miscibility was observed in ternary physical mixtures. The IR analysis confirmed intermolecular interactions between IND and individual polymers. These interactions were found to be intact in ternary systems. These results suggest that the combination of two polymers showing drug–polymer interaction offers synergistic enhancement in amorphous stability and dissolution in ternary solid dispersions. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3511–3523, 2014     

Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions

Purpose

To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems.

Methods

Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (T_g). ¹³C and ¹⁵N solid-state NMR was utilized to investigate changes in local structure and protonation state, while ¹H T₁ and T_1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions.

Results

T_g values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction. ¹⁵N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at ?360.7 ppm (unprotonated) and ?344.4 ppm (protonated). Additionally, ¹H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.

Conclusions

¹⁵N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.

     

Physicochemical Characterization of Hot Melt Extruded Bicalutamide–Polyvinylpyrrolidone Solid Dispersions

Solid molecular dispersions of bicalutamide (BL) and polyvinylpyrrolidone (PVP) were prepared by hot melt extrusion technology at drug‐to‐polymer ratios of 1:10, 2:10, and 3:10 (w/w). The solid‐state properties of BL, physical mixtures of BL/PVP, and hot melt extrudates were characterized using differential scanning calorimetry (DSC), powder X‐ray diffractometry (PXRD), Raman, and Fourier transform infrared (FTIR) spectroscopy. Drug dissolution studies were subsequently conducted on hot melt extruded solid dispersions and physical mixtures. All hot melt extrudates had a single T_g between the T_g of amorphous BL and PVP indicating miscibility of BL with PVP and the formation of solid molecular dispersions. PXRD confirmed the presence of the amorphous form of BL within the extrudates. Conversely, PXRD patterns recorded for physical mixtures showed sharp bands characteristic of crystalline BL, whereas DSC traces had a distinct endotherm at 196°C corresponding to melting of crystalline BL. Further investigations using DSC confirmed solid‐state plasticization of PVP by amorphous BL and hence antiplasticization of amorphous BL by PVP. Experimentally observed T_g values of physical mixtures were shown to be significantly higher than those calculated using the Gordon–Taylor equation suggesting the formation of strong intermolecular interactions between BL and PVP. FTIR and Raman spectroscopy were used to investigate these interactions and strongly suggested the presence of secondary interaction between PVP and BL within the hot melt extrudates. The drug dissolution properties of hot melt extrudates were enhanced significantly in comparison to crystalline BL and physical mixtures. Moreover, the rate and extent of BL release were highly dependent on the amount of PVP present within the extrudate. Storage of the extrudates confirmed the stability of amorphous BL for up to 12 months at 20°C, 40% RH whereas stability was reduced under highly humid conditions (20°C, 65% RH). Interestingly, BL recrystallization after storage under these conditions had no effect on the dissolution properties of the extrudates. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1322–1335, 2010     

Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone)

The physical stability of amorphous molecular level solid dispersions will be influenced by the miscibility of the components. The goal of this work was to understand the effects of temperature and relative humidity on the miscibility of a model amorphous solid dispersion. Infrared spectroscopy was used to evaluate drug–polymer hydrogen bonding interactions in amorphous solid dispersions of felodipine and poly(vinyl pyrrolidone) (PVP). Samples were analyzed under stressed conditions: high temperature and high relative humidity. The glass transition temperature (T_g) of select systems was studied using differential scanning calorimetry (DSC). Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were used to further investigate moisture-induced changes in solid dispersions. Felodipine-PVP solid dispersions showed evidence of adhesive hydrogen bonding interactions at all compositions studied. The drug–polymer intermolecular interactions were weakened and/or less numerous on increasing the temperature, but persisted up to the melting temperature of the drug. Changes in the hydrogen bonding interactions were found to be reversible with changes in temperature. In contrast, the introduction of water into amorphous molecular level solid dispersions at room temperature irreversibly disrupted interactions between the drug and the polymer resulting in amorphous-amorphous phase separation followed by crystallization. DSC, AFM, and TEM results provided further evidence for the occurrence of moisture induced immiscibility. In conclusion, it appears that felodipine-PVP solid dispersions are susceptible to moisture-induced immiscibility when stored at a relative humidity ≥75%. In contrast, the solid dispersions remained miscible on heating. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:169–185, 2010     

Recrystallization of Nifedipine and Felodipine from Amorphous Molecular Level Solid Dispersions Containing Poly(vinylpyrrolidone) and Sorbed Water

Purpose To compare the physical stability of amorphous molecular level solid dispersions of nifedipine and felodipine, in the presence of poly(vinylpyrrolidone) (PVP) and small amounts of moisture. Methods Thin amorphous films of nifedipine and felodipine and amorphous molecular level solid dispersions with PVP were stored at various relative humidities (RH) and the nucleation rate was measured. The amount of water sorbed at each RH was measured using isothermal vapor sorption and glass transition temperatures (T _g) were determined using differential scanning calorimetry. The solubility of each compound in methyl pyrrolidone was measured as a function of water content. Results Nifedipine crystallizes more easily than felodipine at any given polymer concentration and in the presence of moisture. The glass transition temperatures of each compound, alone and in the presence of PVP, are statistically equivalent at any given water content. The nifedipine systems are significantly more hygroscopic than the corresponding felodipine systems. Conclusions Variations in the physical stability of the two compounds could not be explained by differences in T _g. However, the relative physical stability is consistent with differences in the degree of supersaturation of each drug in the solid dispersion, treating the polymer and water as a co-solvent system for each drug compound.     

Physical Stability of Amorphous Solid Dispersions: a Physicochemical Perspective with Thermodynamic,Kinetic and Environmental Aspects

Purpose

Amorphous solid dispersions (ASDs) have been widely used in the pharmaceutical industry for solubility enhancementof poorly water-soluble drugs. The physical stability, however, remainsone of the most challenging issues for the formulation development.Many factors can affect the physical stability via different mechanisms, and therefore an in-depth understanding on these factors isrequired.

Methods

In this review, we intend to summarize the physical stability of ASDsfrom a physicochemical perspective whereby factors that can influence the physical stability areclassified into thermodynamic, kinetic and environmental aspects.

Results

The drug-polymer miscibility and solubility are consideredas the main thermodynamicfactors which may determine the spontaneity of the occurrence of the physical instabilityof ASDs. Glass-transition temperature,molecular mobility, manufacturing process,physical stabilityof amorphous drugs, and drug-polymerinteractionsareconsideredas the kinetic factors which areassociated with the kinetic stability of ASDs on aging. Storage conditions including temperature and humidity could significantly affect the thermodynamicand kineticstabilityof ASDs.

Conclusion

When designing amorphous solid dispersions, it isrecommended that these thermodynamic, kinetic and environmental aspects should be completely investigatedand compared to establish rationale formulations for amorphous solid dispersions with high physical stability.

     

Meloxicam-Paracetamol Binary Solid Dispersion Systems with Enhanced Solubility and Dissolution Rate:Preparation,Characterization, and In Vivo Evaluation

The aim of this work included the improvement of meloxicam solubility and maximizing its pharmacological activity by forming binary solid dispersions with paracetamol. Different binary solid dispersions were prepared using paracetamol as a pharmacologically related coformer with favorable structural, dissolution, and solubility properties. The prepared binary solid dispersions were characterized using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Saturation solubility and dissolution rate were determined for meloxicam-paracetamol binary solid dispersions and compared to each drug individually. The pharmacological effects of meloxicam were enhanced in binary solid dispersions compared to the physical mixture using mice as animal models. This finding could be attributed to the improvement of meloxicam saturation solubility in the binary solid dispersion systems. Solid state characterization demonstrated the formation of amorphous phase with low crystallinity as obtained by XRD data. The solid dispersion prepared by freeze drying at 1:10 molar ratio showed more than sevenfold increase in solubility of meloxicam and more than 65% increase in dissolution rate compared to both generic preparation and physical mixture tablets. Significant differences (P < 0.05) in the analgesic effect represented by the increase in time of licking of forepaws to 7.92 s for the solid dispersion (SD) (F4) system compared to 6.15 and 4.82 s, for physical mixture and control groups were observed, respectively. A significant difference (P < 0.05) in the anti-inflammatory effect was demonstrated for the binary solid dispersion showing more than 50% decrease in the volume of carrageenan-induced tail edema compared to that of the physical mixture. Therefore, the freeze dried binary solid dispersion of meloxicam and paracetamol has shown to increase the analgesic and anti-inflammatory activities as compared to the physical mixture.     

Novel methods for the assessment of miscibility of amorphous drug-polymer dispersions

A typical approach to miscibility analysis of amorphous drug-excipient dispersions involves measuring the glass transition temperature, T_g, using differential scanning calorimetery (DSC). Recently, we discussed two computational methods for the miscibility analysis of amorphous dispersions using X-ray powder diffraction (XRPD). Those methods could be used to qualify an amorphous dispersion as miscible or phase separated, with the implication that miscible dispersions are more stable towards recrystallization. The methods were limited by the need for reference XRPD patterns of both the amorphous drug and excipient. In this work, we propose two additional computational approaches that overcome that limitation and can be used to quantify the degree of miscibility in an amorphous dispersion. The first approach is based on the use of a Pure Curve Resolution Method to extract unknown amorphous references as well as qualify miscibility. The second method, based on Alternate Least Squares, can then be used to quantify the degree of miscibility by determining the nearest neighbor (NN) coordination number for the active pharmaceutical ingredient (API) and excipient. It is proposed that the NN coordination number is related to physical stability. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3373–3386, 2009     

Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA

The aim of this paper was to evaluate physical stability of solid dispersions in respect to the drug, tadalafil (Td), in vinylpyrrolidone and vinyl acetate block copolymer (PVP-VA). Nine solid dispersions of Td in PVP-VA (Td/PVP-VA) varied in terms of quantitative composition (1:9–9:1, w/w) were successfully produced by spray-drying. Their amorphous nature, supersaturated character and molecular level of mixing (a solid solution structure) were subsequently confirmed using DSC, PXRD, SEM and calculation of Hansen total solubility parameters. Due to thermal degradation of both components before the melting point of Td (302.3 °C), an approach based on the drug crystallization from the supersaturated solid dispersion was selected to calculate the solubility of Td in the polymer. Annealing of the Td/PVP-VA solid dispersion (1:1, w/w) at selected temperatures above its T_g resulted in different stable solid dispersions. According to the Gordon–Taylor equation their new T_gs gave the information about the quantitative composition which corresponded to the thermodynamic solubility of Td in PVP-VA at given temperatures of annealing. The obtained relationship was fitted to the exponential function, with the calculated solubility of Td of 20.5% at 25 °C. This value was in accordance with the results of hot stage polarizing light microscopy as well as stability tests carried out at 80 °C and 0% RH, in which Td solid dispersions containing 10–20% of the drug were the only systems that did not crystallize within two months. A thermal analysis protocol utilizing a fast heating rate was shown to generate Td solubility data complementing the solid dispersion method. The Flory–Huggins model applied for the Td/PVP-VA system yielded the solubility value of 0.1% at 25 °C, showing the lack of applicability in this case.     

A Rheological Approach for Predicting Physical Stability of Amorphous Solid Dispersions

Miscibility is an important indicator of physical stability against crystallization of amorphous solid dispersions (ASDs). Currently available methods for miscibility determination have both theoretical and practical limitations. Here we report a method of miscibility determination based on the overlap concentration, c*, which can be conveniently determined from the viscosity-composition diagram. The determined c* values for ASDs of two model drugs, celecoxib and loratadine, with four different grades of polyvinylpyrrolidone (PVP), were correlated strongly with the physical stability of ASDs. This result suggests potential application of the c* concept in guiding the design of stable high drug loaded ASD formulations. A procedure is provided to facilitate broader adoption of this methodology. The procedure is easy to apply and widely applicable for thermally stable binary drug/polymer combinations.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Influence of Glass Forming Ability on the Physical Stability of Supersaturated Amorphous Solid Dispersions

In this study, the influence of the glass-forming ability (GFA) of a drug on its physical stability in a supersaturated solid dispersion was investigated. Nine drugs were classified according to their GFA using their respective critical cooling rate. Their respective solubility in poly(vinylpyrrolidone-co-vinyl acetate) 6:4 (PVPVA64) was predicted using the melting point depression method based on the Flory-Huggins lattice theory. Supersaturated amorphous solid dispersions at a level of 25% w/w drug above saturation solubility in the polymer were prepared by film-casting, and their respective physical stability at temperatures of 10°C or 20°C above or below their respective T_g (dry conditions) was monitored by the use of polarized light microscopy. This study showed that drugs with good GFA (class 3) on average have higher physical stability in supersaturated amorphous solid dispersion compared to drug with modest GFA (class 2), which in turn have higher physical stability in supersaturated amorphous solid dispersion than drugs with poor GFA (class 1). These results indicate that the GFA of a drug and its physical stability in a supersaturated amorphous solid dispersion stored at a temperature above or below its T_g are correlated.     

Drug–Polymer Solubility and Miscibility: Stability Consideration and Practical Challenges in Amorphous Solid Dispersion Development

Drug–polymer solid dispersion has been demonstrated as a feasible approach to formulate poorly water-soluble drugs in the amorphous form, for the enhancement of dissolution rate and bioperformance. The solubility (for crystalline drug) and miscibility (for amorphous drug) in the polymer are directly related to the stabilization of amorphous drug against crystallization. Therefore, it is important for pharmaceutical scientists to rationally assess solubility and miscibility in order to select the optimal formulation (e.g., polymer type, drug loading, etc.) and recommend storage conditions, with respect to maximizing the physical stability. This commentary attempts to discuss the concepts and implications of the drug–polymer solubility and miscibility on the stabilization of solid dispersions, review recent literatures, and propose some practical strategies for the evaluation and development of such systems utilizing a working diagram.     

Miniaturized screening of polymers for amorphous drug stabilization (SPADS): Rapid assessment of solid dispersion systems

PurposeDevelopment of a novel, rapid, miniaturized approach to identify amorphous solid dispersions with maximum supersaturation and solid state stability.MethodThree different miniaturized assays are combined in a 2-step decision process to assess the supersaturation potential and drug–polymer miscibility and stability of amorphous compositions. Step 1: SPADS dissolution assay. Drug dissolution is determined in 96-well plates to detect systems that generate and maintain supersaturation. Promising combinations graduate to step 2. Step 2: SPADS interaction and SPADS imaging assays. FTIR microspectroscopy is used to study intermolecular interactions. Atomic force microscopy is applied to analyze molecular homogeneity and stability. Based on the screening results, selected drug–polymer combinations were also prepared by spray-drying and characterized by classical dissolution tests and a 6-month physical stability study.ResultsFrom the 7 different polymers and 4 drug loads tested, EUDRAGIT® E PO at a drug load of 20% performed best for the model drug CETP(2). The classical dissolution and stability tests confirmed the results from the miniaturized assays.ConclusionThe results demonstrate that the SPADS approach is a useful de-risking tool allowing the rapid, rational, time- and cost-effective identification of polymers and drug loads with appropriate dual function in supersaturation performance and amorphous drug stabilization.     

Characterization and dissolution behavior of nifedipine and phosphatidylcholine binary systems

Physicochemical properties and the dissolution behavior of binary systems of nifedipine (NIF) and dipalmitoylphosphatidylcholine (DPPC) or dimyristoylphosphatidylcholine (DMPC) as physical mixtures, solid dispersions and ground mixtures at 9:1 w/w were investigated. The drug and formulations were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and differential thermal analysis (DTA). The dissolution and solubility of NIF was increased in the order physical mixture < solid dispersion < ground mixture. The powder X-ray diffraction patterns and FTIR spectra indicated absence of major crystalline or molecular changes of NIF or the PCs. The fraction of NIF dissolved after 1 h was approximately 30 and 34% from NIF/DMPC and NIF/DPPC ground mixtures, respectively, and the dissolution was only slightly reduced from NIF/DPPC, 9.75:0.25 w/w systems. The crystal lattice parameter, c, of DPPC and DMPC in the solid dispersion was longer than that of PC alone but each was considered to be in an amorphous state in the ground mixture because of the absence of an X-ray diffraction peak. Full-width at half-maximum (half width) of the X-ray diffraction peak of NIF in the ground mixture was greater than NIF in the physical mixture or solid dispersion, suggesting that the lattice distortion of NIF crystals was increased by grinding. Thermal analysis confirmed the crystalline state of DPPC and DMPC in the physical mixture and the solid dispersion but an amorphous state in the ground mixture. Thus, an increase in lattice distortion of NIF crystals due to grinding and an amorphous state of DPPC or DMPC in the ground mixtures are considered mainly responsible for the larger increase in dissolution rate and extent of dissolution of NIF after 1 h compared to the solid dispersion formulation.     

Producing Amorphous Solid Dispersions via Co-Precipitation and Spray Drying: Impact to Physicochemical and Biopharmaceutical Properties

Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low-solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and C_max. Based on the summarized data, we conclude that for some APIs, co-precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics.     

Current status of supersaturable self-emulsifying drug delivery systems

为了提高难溶性药物阿瑞匹坦(aprepitant,APR)的溶解度,解决其酸中溶出、碱中结晶沉淀的问题,选择不同功能的聚合物载体制备三元固体分散体,并对其进行性能考察。

采用溶剂-蒸发法制备二元固体分散体,以溶出度和溶出速度为指标,筛选具有增溶功能的载体材料。通过介质转移法考察各聚合物在不同浓度的药物溶液中的抑晶性能,筛选出最佳的沉淀抑制剂。确定药载比,将APR、溶出促进剂及沉淀抑制剂以不同比例混合,采用热熔挤出技术制备三元固体分散体,以溶出度和抑晶时间为指标,优选出三元固体分散体处方。经X射线衍射技术确认药物在载体中的存在状态,考察该三元固体分散体在模拟肠液中的动态溶解度和加速条件下的物理稳定性。

亲水性聚合物PVP K30制备的二元固体分散体溶出速度快,增溶效果佳,肠溶性聚合物HPMCAS显示出优越的抑晶作用,延长了APR的过饱和点,质量比为1∶1∶3(APR∶PVP K30∶HPMCAS)的三元固体分散体在酸中迅速完全释放(120 min溶出95%),相对于原料药显著提高了溶出度和溶出速率,当介质pH值转为6.8后,三元固体分散体完全释放并在6 h内维持溶液处于高过饱和的稳定状态,药物以无定形形式存在于载体基质中,同时能在加速条件下保持≥3个月的无定形状态。

基于不同聚合物的理化特性,本研究制备的三元固体分散体通过协调溶出速率和结晶抑制效果,不仅显著提高APR的溶解度,而且能解决APR在胃中溶出、肠中沉淀析晶的问题,具有良好的溶出特性。

     

Effect of Different “States” of Sorbed Water on Amorphous Celecoxib

Glass transition temperature (T_g) of an amorphous drug is a vital physical phenomenon that influences its visco-elastic properties, physical, and chemical stability. Water acts as a plasticizer for amorphous drugs thus increasing their recrystallization kinetics. This reduces the solubility advantage of an amorphous drug. Hence, there is an interest in understanding the relationship between water content and T_g of amorphous drug. We have studied the effect of “state” of sorbed water on T_g of amorphous celecoxib (ACLB). ACLB was allowed to sorb water at relative humidity of 33%, 53%, 75%, and 93%. ALCB showed biphasic sorption of water designated as “bound” and “solvent-like” state of water associated with ACLB. Molecular modeling studies provided deeper insights into the interaction of water with ACLB. A distinct co-relationship between the state of water and its plasticization capacity was observed. Bound state of water had a very profound effect on the fall in experimentally observed T_g (T_g-exp) value. Solvent-like state of water had little impact on T_g-exp value. T_g of ACLB–water mixture was predicted by Gordon–Taylor equation (T_g-pre). The deviations in T_g-exp and T_g-pre were correlated to volume non-additivity and non-ideal mixing. This study has implications on the development of formulations based on amorphous forms.     

Investigation of Ethylene Oxide-co-propylene Oxide for Dissolution Enhancement of Hot-Melt Extruded Solid Dispersions

The optimal design of amorphous solid dispersion formulations requires the use of excipients to maintain supersaturation and improve physical stability to ensure shelf-life stability and better absorption during intestinal transit, respectively. Blends of excipients (surfactants and polymers) are often used within pharmaceutical products to improve the oral delivery of Biopharmaceutical Classification System class II drugs. Therefore, in this study, a dissolution enhancer, poloxamer 407 (P407), was investigated to determine its effect on the dissolution properties and on the amorphous nature of the active pharmaceutical ingredient contained in the formulation. Phase solubility studies of indomethacin (INM) in aqueous solutions of P407 and poly(vinylpyrrolidone-vinyl acetate copolymer) showed an increase in the kinetic solubility of INM compared with the pure drug at 37°C with a K_a value of 0.041 μg/mL. The solid dispersions showed a higher dissolution rate when compared to pure and amorphous drugs when performed in pH buffer 1.2 with a kinetic solubility of 21 μg/mL. The stability data showed that the amorphous drug in solid solutions with poly(vinylpyrrolidone-vinyl acetate copolymer) and P407 remained amorphous, and the %P407 loading had no effect on the amorphous stability of INM. This study concluded that the amorphous solid dispersion contributed to the increased solubility of INM.