A Mechanistic Model for Predicting the Physical Stability of Amorphous Solid Dispersions

In this paper, we establish a mechanistic model for the prediction of amorphous solid dispersion (ASD) stability. The novel approach incorporates fundamental physical parameters, principally supersaturation, diffusivity, and interfacial energy, to model crystallization in ASDs accounting for both kinetic and thermodynamic drivers. API dependent decoupling coefficients were also considered which allowed dynamic mechanical analysis to probe molecular mobility, with viscosity measurements, across an exceptionally broad range of temperatures to support ASD stability simulations. ASDs are multicomponent systems in which the amorphous form of active pharmaceutical ingredients (APIs) are molecularly dispersed within a carrier. This gives rise to a transiently supersaturated API solution upon dissolution which increases the driving force for oral absorption and results in increased bioavailability as compared to that of the crystalline API. A major shortcoming of ASDs, however, is that there is the potential for amorphous APIs to revert to their more stable crystalline form during storage, despite the use of polymer carriers to stabilize formulations and limit recrystallization. Hot melt extrusion (HME) has been employed as the preparation method for ASDs used in this study as it is well-suited for the formation of uniform dispersions. The ASDs were stored under controlled temperature conditions, in the absence of humidity, to determine recrystallization kinetics. Our mechanistic model, considering both crystal nucleation and growth processes, describes temporal ASD stability through a system of coupled differential equations that connect the physiochemical properties of the ASD system to drug recrystallization. The model and prolonged time scale of crystallization observed highlight the importance of considering both thermodynamic and kinetic factors in the preparation of stable ASDs. Experimental observations were found to be in good agreement with predictions of the model confirming its utility in predicting the temporal physical stability of amorphous solid dispersions through a mechanistic lens.     

非晶固体分散体技术的研究现状

提高药物的溶解度和生物利用度是制剂研究的重要挑战.非晶固体分散体(ASD)能极大增加药物的溶解度和溶出速度,从而改善其生物利用度,被广泛用于难溶性药物的递送.ASD的成功必须满足两点要求:良好的物理稳定性以及良好的溶出以获得较高的生物利用度.本文主要综述ASD的制备方法,表征技术,物理稳定性以及制剂设计理论,以期为AS...     

Characterization and Physical Stability of Spray Dried Solid Dispersions of Probucol and PVP-K30

The main purpose of this study was to obtain stable, well-characterized solid dispersions (SDs) of amorphous probucol and polyvinylpyrrolidone K-30 (PVP-K30) with improved dissolution rates. A secondary aim was to investigate the flow-through dissolution method for in-vitro dissolution measurements of small-sized amorphous powders dispersed in a hydrophilic polymer. SDs were prepared by spray drying solutions of probucol and different amounts of PVP-K30. The obtained SDs were characterized by dissolution rate measurements in a flow-through apparatus, X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), particle sizing (laser diffraction) and Brunauer-Emmett-Teller Method (BET) and results were compared with starting material and a physical mixture. The physical stability was monitored after storage at 25°C and 60% RH for up to 12 weeks. The flow-through method was found suitable as dissolution method. All SDs showed improved in-vitro dissolution rates when compared to starting material and physical mixtures. The greatest improvement in the in-vitro dissolution rate was observed for the highest polymer to drug ratio. By means of the results from XRPD and DSC, it was argued that the presence of amorphous probucol improved the dissolution rate, but the amorphous state could not fully account for the difference in dissolution profiles between the SDs. It was suggested that the increase in surface area due to the reduction in particle size contributed to an increased dissolution rate as well as the presence of PVP-K30 by preventing aggregation and drug re-crystallization and by improving wettability during dissolution. The stabilizing effect of the polymer was verified in the solid state, as all the SDs retained probucol in the amorphous state throughout the entire length of the stability study.     

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.     

Moisture-Induced Amorphous Phase Separation of Amorphous Solid Dispersions: Molecular Mechanism,Microstructure, and Its Impact on Dissolution Performance

Amorphous phase separation (APS) is commonly observed in amorphous solid dispersions (ASD) when exposed to moisture. The objective of this study was to investigate: (1) the phase behavior of amorphous solid dispersions composed of a poorly water-soluble drug with extremely low crystallization propensity, BMS-817399, and PVP, following exposure to different relative humidity (RH), and (2) the impact of phase separation on the intrinsic dissolution rate of amorphous solid dispersion. Drug-polymer interaction was confirmed in ASDs at different drug loading using infrared (IR) spectroscopy and water vapor sorption analysis. It was found that the drug-polymer interaction could persist at low RH (≤75% RH) but was disrupted after exposure to high RH, with the advent of phase separation. Surface morphology and composition of 40/60 ASD at micro-/nano-scale before and after exposure to 95% RH were also compared. It was found that hydrophobic drug enriched on the surface of ASD after APS. However, for the 40/60 ASD system, the intrinsic dissolution rate of amorphous drug was hardly affected by the phase behavior of ASD, which may be partially attributed to the low crystallization tendency of amorphous BMS-817399 and enriched drug amount on the surface of ASD. Intrinsic dissolution rate of PVP decreased resulting from APS, leading to a lower concentration in the dissolution medium, but supersaturation maintenance was not anticipated to be altered after phase separation due to the limited ability of PVP to inhibit drug precipitation and prolong the supersaturation of drug in solution. This study indicated that for compounds with low crystallization propensity and high hydrophobicity, the risk of moisture-induced APS is high but such phase separation may not have profound impact on the drug dissolution performance of ASDs. Therefore, application of ASD technology on slow crystallizers could incur low risks not only in physical stability but also in dissolution performance.     

Characterization and Physical Stability of Tolfenamic Acid-PVP K30 Solid Dispersions

Obtaining a stable formulation with high bioavailability of a poorly water-soluble drug often presents a challenge to the formulation scientist. Transformation of the drug into its more soluble high-energy amorphous form is one method used for improving the dissolution rate of such compounds. The present study uses the spray-drying technique for preparation of solid dispersions (SDs) of tolfenamic acid (TA) and polyvinylpyrrolidone K-30 (PVP). The SDs and TA in the form of a spray-dried powder were initially characterized and compared with a physical mixture and starting materials. Stability of the SDs was monitored over 12 weeks at 25°C and 60% RH. XRPD studies revealed changes in solid state during the formation of the SDs and indicated the presence of TA in the amorphous state. FTIR, together with TGA, suggested molecular interactions (hydrogen-bonding) in the SDs. Dissolution studies proved an increase in the dissolution rate of TA from all SDs. The SDs with higher content of PVP retained TA in the amorphous state throughout the stability study. However, SDs with lower content showed recrystallization of TA after 1 week. Thus, this study reveals the possibility of preparing stable SDs of amorphous TA in PVP with improved dissolution rate.     

尼群地平固体分散物溶出度及稳定性的研究

采用固体分散技术制备了 2种尼群地平固体分散物 ,体外溶出速率均有显著增加 ,X 射线衍射实验表明 2种固体分散物均以非晶状态存在 .稳定性实验表明 ,固体分散物Ⅰ较稳定 ,固体分散物Ⅱ老化现象严重     

过程性因素对固体分散体稳定性的影响

固体分散体是改善难溶性药物溶解度、溶出行为和生物利用度的有效途径,但固体分散体稳定性差已成为制约以固体分散技术为基础的给药系统市场化的瓶颈问题。本文探讨制备方法、制剂工艺、储存条件等过程性因素对固体分散体的重结晶、药物成分含量、溶出、外观等稳定性的影响,为固体分散体研究与开发提供指导。     

尼群地平固体分散体体外溶出度研究

目的:选择尼群地平固体分散体适宜的体外溶出介质。方法:测定尼群地平在多种溶出介质中的溶解度，通过体外溶出度试验比较尼群地平固体分散体在不同溶出介质中的溶出行为。结果:溶出介质1.0%和0.5%的十二烷基硫酸钠(SDS)水溶液可以满足“漏槽”条件，但药物释放较快，固体分散体间的溶出行为差异不明显；0.3%的SDS水溶液可以保证药物的全部溶出，且可以明显区别各固体分散体之间的溶出差异。结论:选用0.3%的SDS水溶液作为溶出介质，便于通过溶出度试验来筛选固体分散体处方。     

尼莫地平固体分散物的研究

尼莫地平临床上主要用于防治缺血性脑血管疾病．该药为难溶性药物，生物利用度低，本文采用了固体分散技术制备了尼莫地平两种固体分散物，其体外溶出速率１０分钟以内达８０％以上，较市售片有显著提高．两种固体分散物中，固体分散物Ⅰ为本实验室研制，固体分散物Ⅱ参照国内、外文献用ＰＶＰ为载体制备．两种固体分散物均能明显提高尼莫地平的体外溶出速率，但固体分散物Ⅱ易于老化，经相对湿度ＲＨ７５％４０℃贮藏３个月溶出速率明显下降，同样条件下，固体分散物Ⅰ则无明显变化．二种固体分散物Ｘ－射线衍射图谱表明尼莫地平以非晶体状态存在，而在ＲＨ７５％４０℃条件下放置３个月后，固体分散物ⅡＸ－射线衍射图谱出现了尼莫地平结晶峰．     

Using Acetone/Water Binary Solvent to Enhance the Stability and Bioavailability of Spray Dried Enzalutamide/HPMC-AS Solid Dispersions

We demonstrated a facile approach, by adjusting the solvent ratio of water/acetone binary mixture, to alter the intermolecular interactions between Enzalutamide (ENZ) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) for spray drying process, which can be readily implemented to produce spray-dried dispersions (SDD) with enhanced stability and bioavailability. The prepared SDD of ENZ/HPMC-AS were examined systematically in terms of particle size, morphology, dissolution, solubility, stability, and bioavailability. Our results show that the introduction of water (up to 30% volume fraction) can effectively reduce the hydrodynamic diameter of HPMC-AS from approximately 220 nm to 160 nm (a reduction of c.a. 20%), which increases the miscibility of the drug and polymer, delaying or inhibiting the crystallization of ENZ during the spray drying process, resulting in a homogeneous amorphous phase. The benefits of using acetone/water binary mixture were subsequently evidenced by an increased specific surface area, improved dissolution profile and relative bioavailability, enhanced stability, and elevated drug release rate. This fundamental finding underpins the great potential of using binary mixture for spray drying process to process active pharmaceutical ingredients (APIs) that are otherwise challenging to handle.     

三维有序大孔壳聚糖/尼莫地平固体分散体的研究

目的制备孔径为470nm的三雏有序大孔壳聚糖／尼莫地平的固体分散体,研究其释药特点、稳定性和药动学。方法利用溶剂蒸发法制备固体分散体,通过药物释放试验考察固体分散体在模拟胃肠液介质中的释放行为;通过含量测定、X-射线衍射和溶出试验检查固体分散体的稳定性;大鼠分别给予自制固体分散体和市售片粉末,测定血药浓度。结果固体分散体在pH6.8的介质中的溶出度明显比pH1.2和pH4.5介质中高,在梯度pH介质中的释药曲线类似阶梯型;结晶度和溶出度在考察时间内基本无变化;自制固体分散体的AUC0.12h是市售制剂的1.91倍,具有长效作用。结论自制固体分散体稳定性良好,能够提高尼莫地平的大鼠口服生物利用度。     

Correlationship of Drug-Polymer Miscibility,Molecular Relaxation and Phase Behavior of Dipyridamole Amorphous Solid Dispersions

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 (τ^β) 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 (T_g) 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.     

In vitro Dissolution Studies on Solid Dispersions of Mefenamic Acid

Solid dispersions of mefanamic acid with a water-soluble polymer polyvinyl pyrrolidine and a super disintegrant, primojel were prepared by common solvent and solvent evaporation methods employing methanol as the solvent. The dissolution rate and dissolution efficiency of the prepared solid dispersions were evaluated in comparison to the corresponding pure drug. Solid dispersions of mefenamic acid showed a marked enhancement in dissolution rate and dissolution efficiency. At 1:4 ratio of mefenamic acid-primojel a 2.61 fold increase in the dissolution rate of mefenamic acid was observed with solid dispersion. The solid dispersions in combined carriers gave much higher rates of dissolution than super disintegrants alone. Mefanamic acid-primojel-polyvinyl pyrrolidine (1:3.2:0.8) solid dispersion gave a 4.11 fold increase in the dissolution rate of mefenamic acid. Super disintegrants alone or in combination with polyvinyl pyrrolidine could be used to enhance the dissolution rate of mefenamic acid.     

Use of Surfactants as Plasticizers in Preparing Solid Dispersions of Poorly Soluble API: Stability Testing of Selected Solid Dispersions

Purpose The purpose of the study is to evaluate the effect of surfactant-plasticizers on the physical stability of amorphous drug in polymer matrices formed by hot melt extrusion.Method Solid dispersions of a poorly soluble drug were prepared using PVP-K30, Plasdone-S630, and HPMC-E5 as the polymeric carriers and surfactants as plasticizers. The solid dispersions were produced by hot melt extrusion at temperatures 10°C above and below the glass transition temperature (Tg) of the carrier polymers using a 16 mm-Haake Extruder. The surfactants tested in this study included Tween-80 and Docusate Sodium. The particle size of the extrudate was reduced to have mean of 100–200 micron. The physical stability of the solid dispersions produced was monitored at 30°C/60% for six-months and at 60°C/85% for two-months in open HDPE bottles. Modulated differential scanning calorimetry, polarized light microscopy, powder X-ray diffraction and dissolution testing was performed to assess the physical stability of solid dispersions upon stress testing.Results The dispersions containing HPMC-E5 were observed especially to be susceptible to physical instability under an accelerated stress conditions (60°C/85%RH) of the solid dispersion. About 6% conversion of amorphous drug to crystalline form was observed. Consequently, the system exhibits similar degree of re-crystallization upon addition of the surfactant. However, under 30°C/60%RH condition, the otherwise amorphous Drug-HPMC-E5 system has been destabilized by the addition of the surfactant. This effect is much more reduced in the extruded solid dispersions where polymeric carriers such as Plasdone S-603 and PVP-K30 (in addition to surfactants) are present. Furthermore, the drug release from the solid dispersions was unaffected at the stress conditions reported above.Conclusions Possible reasons for the enhanced stability of the dispersions are due to the surfactants ability to lower the viscosity of the melt, increase the API solubility and homogeneity in the carrier polymer. In contrast, while it is possible for the surfactants to destabilize the system by lowering the Tg and increasing the water uptake, the study confirms that this effect is minimal. By and large, the surfactants appear to be promising plasticizers to produce solid dispersions by hot melt extrusion, in so doing improving dissolution rate without compromising the physical stability of the systems.     

冬凌草甲素固体分散体的制备及溶解性能研究

目的 采用固体分散技术,提高冬凌草甲素的体外溶解性能。方法 分别以聚乙二醇6000(PEG6000)、聚乙烯吡咯烷酮K30(PVPK30)为载体,制备冬凌草甲素固体分散体。采用紫外分光光度法进行含量测定,差示热分析法鉴别药物在载体中的存在状态,并进行溶解度、体外溶出速率实验。结果 两种载体的固体分散体均能增加药物的溶解度和溶出速率,冬凌草甲素在载体中以高度分散状态存在。结论 以 PVPK30为载体制备的冬凌草甲素固体分散体体外溶解度和溶出速率明显提高。     

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.     

坎地沙坦固体分散体的制备及溶出度、稳定性研究

目的利用固体分散技术提高坎地沙坦的溶解性。方法以体外溶出度为指标,通过单因素试验,考察处方和工艺因素对坎地沙坦固体分散体中药物溶出的影响,运用正交试验选定坎地沙坦固体分散体的最优处方;采用FTIR、DSC、XRD分析技术对药物与载体间的相互作用及药物在固体分散体中的存在状态进行鉴定,探讨固体分散体的增溶机制,考察固体分散体的稳定性。结果以聚乙烯吡咯烷酮（PVPK30）为载体,二氯甲烷：甲醇：乙醇－2：2：l为混合溶剂制备的固体分散体溶出度lh可达99％;红外分析表明坎地沙坦与PVPK30间有氢键形成;DSC及XRD表征表明坎地沙坦以微晶或无定形态分散于PVPK30中;稳定性加速试验显示固体分散体经过30d后XRD显示药物无明显的团聚,仍以微晶或无定形态存在。结论固体分散技术能有效提高坎地沙坦的溶出度。制得的坎地沙坦固体分散体为一稳定体系,具有实际应用价值。     

Enhanced Drug Dissolution and Bulk Properties of Solid Dispersions Granulated with a Surface Adsorbent

A combination of solid dispersion and surface adsorption techniques was used to enhance the dissolution of a poorly water-soluble drug, BAY 12-9566. In addition to dissolution enhancement, this method allows compression of the granulated dispersion into tablets. Gelucire 50/13 (polyglycolized glycerides) was used as the solid dispersion carrier. Hot-melt granulation was performed to adsorb the melt of the drug and Gelucire 50/13 onto the surface of Neusilin US2 (magnesium alumino silicate), the surface adsorbent. Dispersion granules using various ratios of drug–Gelucire 50/13–Neusilin US2 were thus prepared. The dissolution profiles of BAY 12-9566 from the dispersion granules and corresponding physical mixtures were evaluated using USP Type II apparatus at 75 rpm. The dissolution medium consisted of 0.1 N hydrochloric acid (HCl) with 1% w/v sodium lauryl sulfate (SLS). Dissolution of BAY 12-9566 from the dispersion granules was enhanced compared to the physical mixture. The dissolution of BAY 12-9566 increased as a function of increased Gelucire 50/13 and Neusilin US2 loading and decreased with increased drug loading. In contrast to the usually observed decrease in dissolution on storage, an enhancement in dissolution was observed for the dispersion granules stored at 40°C/75% relative humidity (RH) for 2 and 4 weeks. Additionally, the flow and compressibility properties of dispersion granules were improved significantly when compared to the drug alone or the corresponding physical mixture. The ternary dispersion granules were compressed easily into tablets with up to 30% w/w drug loading. The extent of dissolution of drug from these tablets was greater than that from the uncompressed dispersion granules.     

Mechanical Properties and Tableting Behavior of Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (T_g) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content. This in turn significantly influenced tablet quality. Water reduced both the hardness and T_g of ASDs, and the APAP loading level corresponding to the transition to the softening mechanism was lower at a higher relative humidity. Overall, the mechanical properties, rather than the thermal properties, better represent the plasticization/antiplasticization effect of small molecule to ASDs.