Impact of process variables on the micromeritic and physicochemical properties of spray‐dried microparticles – Part II. Physicochemical characterisation of spray‐dried materials

Objectives In this work we investigated the residual organic solvent content and physicochemical properties of spray‐dried chlorothiazide sodium (CTZNa) and potassium (CTZK) salts. Methods The powders were characterised by thermal, X‐ray diffraction, infrared and dynamic vapour sorption (DVS) analyses. Solvent levels were investigated by Karl–Fischer titration and gas chromatography. Key findings Spray‐drying from water, methanol (MeOH) and mixes of MeOH and butyl acetate (BA) resulted in amorphous microparticles. The glass transition temperatures of CTZNa and CTZK were ～192 and ～159°C, respectively. These materials retained their amorphous nature when stored at 25°C in dry conditions for at least 6 months with no chemical decomposition observed. DVS determined the critical relative humidity of recrystallisation of CTZNa and CTZK to be 57% RH and 58% RH, respectively. The inlet temperature dependant oxidation of MeOH to formaldehyde was observed; the formaldehyde was seen to deposit within the amorphous matrix of spray‐dried product. Spray‐drying in the open blowing mode coupled with secondary drying resulted in a three‐fold reduction in residual BA (below pharmacopoeial permitted daily exposure limit) compared to spray‐drying in the closed mode. Conclusions Experiments showed that recirculation of recovered drying gas increases the risk of deposition of residual solvents in the spray‐dried product.     

PVP K30 对葛根黄豆苷元溶解度和溶出的影响

目的研究PVP K30 对葛根黄豆苷元水溶解性和溶出性质的影响.方法测量葛根黄豆苷元及其固体分散体、物理混合物的水溶解度和溶出速度,并用X-射线衍射、IR表征药物与PVP在固态条件下的相互作用.结果 Gibbs自由能和转移焓均小于零,表明葛根黄豆苷元从磷酸盐缓冲溶液中转移到PVP的磷酸盐缓冲溶液中是一自发的过程;X-射线衍射结果表明葛根黄豆苷元在PVP固体分散体(药物∶PVP < 1∶5)中以无定形形式存在; IR结果表明葛根黄豆苷元的羟基与PVP分子中的C=O之间存在相互作用.结论葛根黄豆苷元的PVP分散体可大大提高药物溶解度和溶出速度.     

Solubility of Small-Molecule Crystals in Polymers: <Emphasis Type="SmallCaps">d</Emphasis>-Mannitol in PVP,Indomethacin in PVP/VA,and Nifedipine in PVP/VA

Objective  Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult. Method  Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods. Results  The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA. Conclusion  A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.     

PVP K30对葛根黄豆苷元增溶的研究

研究了葛根黄豆苷元(1)在不同温度、不同浓度的PVP K30—磷酸盐缓冲液中的溶解度，1溶解度随辅料浓度的增大而明显增大。溶解度数据经热力学方法处理，表明这是个自发过程。采用溶剂法，以PVP K30为载体制备1固体分散体，考察固体分散体中1的溶解度和溶出度。与其本身相比，固体分散体中1溶解度显著提高，溶出速度明显增大。     

Development of spray‐ and freeze‐dried high‐concentration sesamol emulsions and antioxidant evaluation in fibroblasts and UV‐exposed rat skin slices

Dry sesamol emulsions were synthesized from several combinations of saccharose with hydroxypropylmethylcellulose (HPMC) or sodium caseinate (SC) using spray‐drying techniques at 120° to 180°C, or freeze‐drying. On the basis of physical characteristics such as droplet size distribution, residual moisture, and microscopic structure, the best material was obtained when spray‐drying was applied at either 150° or 180°C with SC or HPMC as excipients, respectively. The extent to which the antioxidant properties of free sesamol towards a set of free radicals (galvinoxyl, diphenylpicrylhydrazyl, superoxide, and hydroxyl) were altered in the starting and reconstituted liquid emulsions submitted to normal storage or pre‐exposed to a flux hydroxyl radicals was investigated. Emulsions were further evaluated for their antioxidant properties in cultured 3T3 murine fibroblasts and in an ex vivo model of ultraviolet irradiated rat skin. It was found that, in the material having the best physical properties, encapsulation was decisive in: (1) improving the overall antioxidant behavior of reconstituted versus starting liquid emulsions: (2) sparing sesamol consumption due to free radical attack; and (3) significantly protecting cells and skin against free radical‐ or irradiation‐induced enzymatic release and/or lipid peroxidation. Demonstrating a high activity at high dilutions where interactions of excipient become negligible, the new emulsions could be of great interest in sesamol‐based pharmacology or topical applications. Drug Dev Res 69:251–266, 2008. © 2008 Wiley‐Liss, Inc.     

Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and d-mannitol

Aim of the present study was to improve the solubility and dissolution rate of poorly water soluble, BCS class-II drug Ketoprofen (KETO) by solid-dispersion approach. Solid dispersions were prepared by using polyvinylpyrrolidone K30 (PVP K30) and d-mannitol in different drugs to carrier ratios. Dispersions with PVP K30 were prepared by kneading and solvent evaporation techniques, whereas solid dispersions containing d-mannitol were prepared by kneading and melting techniques. These formulations were characterized in the liquid state by phase-solubility studies and in the solid state by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM). The aqueous solubility of KETO was favored by the presence of both carriers. The negative values of Gibbs free energy illustrate the spontaneous transfer from pure water to the aqueous polymer environment. Solid state characterization indicated KETO was present as fine particles in d-mannitol solid dispersions and entrapped in carrier matrix of PVP K30 solid dispersions. In contrast to the very slow dissolution rate of pure KETO, dispersions of drug in carriers considerably improved the dissolution rate. This can be attributed to increased wettability and dispersibility, as well as decreased crystallinity and increase in amorphous fraction of drug. Solid dispersions prepared with PVP K30 showed the highest improvement in dissolution rate of KETO. Even physical mixtures of KETO prepared with both carriers also showed better dissolution profiles than those of pure KETO.     

Effect of physical properties of troglitazone crystal on the molecular interaction with PVP during heating

This study examined the effect of physical properties of troglitazone drug substance on the molecular interaction with polyvinylpyrrolidone K30 (PVP) during preparation by a closed melting method. Milling was conducted using impact and jet mills to change the physical properties of troglitazone, such as particle size, specific surface area, surface free energy and acidic-basic parameters. Solid dispersions (SDs) prepared from milled troglitazone, irrespective of milling method, showed almost 100% dissolution when not less than 7.5% of water was added during heating. SDs prepared from unmilled troglitazone showed almost 100% dissolution when not less than 12.8% of water was added during heating. Physical mixture (PM) containing unmilled troglitazone must be heated above at least 50 degrees C higher than the glass transition temperature (T(g)) of PVP to obtain an SD showing 100% dissolution, while PMs containing milled troglitazone could be heated above only 20 degrees C higher than the T(g) of PVP to obtain an SD showing 100% dissolution. The melting points of troglitazone in PMs containing milled troglitazone, irrespective of milling method, were lower than those in PMs containing unmilled troglitazone. These results indicated that specific interaction could occur more easily during heating between milled troglitazone and PVP during preparation by a closed melting method. In addition, Fourier transform infrared study indicated that hydrogen bonding could occur between the N-H of troglitazone and the C=O of PVP.     

Application of Online Near Infrared for Process Understanding of Spray-Drying Solution Preparation

Solution preparation is the first unit operation of the manufacturing process for spray-dried solid dispersions. Visual inspection and offline high-performance liquid chromatography analysis are routinely used to assess the solution preparation end point as well as the final solution composition. However, the accuracy and appropriateness of these approaches are challenged by the scale of production and solvent evaporation during sample handling. Thus an appropriate online process analytical tool is needed to improve process and quality control for the solution preparation process. The objective of this report is to develop near infrared (NIR) models for real-time monitoring of the spray solution preparation process. These models were built and refined via 2 different experiments designs with different production scale. The potency of spray-dried intermediate was analyzed by high-performance liquid chromatography and used to verify the quantitative model. The results indicated that the quantitative NIR models can be used to predict the active pharmaceutical ingredient concentration of the final spray solution accurately with a standard error of prediction of 2.4 wt%. Based on this investigation, online NIR was deemed to be a suitable analytical tool on process and quality control for spray solution preparation.     

Development of an itraconazole‐loaded gelatin microcapsule with enhanced oral bioavailability: physicochemical characterization and in‐vivo evaluation

Objectives The aim of this study was to develop a novel itraconazole‐loaded gelatin microcapsule without ethanol with enhanced oral bioavailability. Methods Various gelatin microcapsules were prepared using a spray‐drying technique. Their physicochemical properties, dissolution, characteristics and pharmacokinetics in rats were evaluated and compared with those of a commercial product. Key findings The gelatin microcapsule at a weight ratio for itraconazole/gelatin/citric acid of 1 : 3 : 0.3 was spherical in shape with a smooth surface and inner hole, and gave a maximum drug solubility of about 700 μg/ml. The gelatin microcapsule dramatically increased the initial dissolution rate of itraconazole compared with a commercial product in simulated gastric fluids (pH 1.2). Moreover, at the same dose as the commercial product, it gave significantly higher initial plasma concentrations, C_max and AUC of itraconazole in rats than did the commercial product, indicating that providing the drug in the gelatin microcapsule caused enhanced absorption in rats. At half dose, it gave similar AUC, C_max and T_max values to the commercial product, suggesting that it was bioequivalent to the commercial product in rats. Conclusions The itraconazole‐loaded gelatin microcapsule without ethanol developed using a spray‐drying technique at half the dose of the commercial product can deliver itraconazole in a pattern that allows fast absorption in the initial phase, making it bioequivalent to the commercial product.     

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.     

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.     

乙肝清HPMC K4M/PVP K30骨架缓释片的研制与体外评价

目的 进行乙肝清HPMC K4M/PVP K30骨架缓释片的研制与体外评价。方法 以中药赶黄草和贯叶连翘的提取物为原料药,以HPMC K4M和PVP K30两种粘度不同,水合行为差异较大的亲水高分子材料联合使用作为骨架材料,制备缓释12 h的“乙肝清骨架缓释片”。 以“HPMC+PVP K30”总量在处方中的百分量和HPMC在“HPMC+PVP K30” 总量中的百分量为考察因素,通过处方单因素考察和星点设计—效应面法进行优化,得到最佳的制剂处方。并通过均一性实验和体外释药行为研究进行体外评价。结果 本片剂优化处方中最低HPMC K4M与PVP K30用量不得低于20%。最佳制剂处方为骨架材料HPMC+PVP K30总量占片剂质量的27.03%,HPMC占HPMC+PVP K30总量的49.04%。本处方具有良好的重现性与稳定性;片剂药物释放符合一级释放模型。结论 制备了载药量40%的乙肝清提取物缓释片,并优化得到了其最佳的制剂处方。     

The antithrombosis effect of dehydroandrographolide succinate: in vitro and in vivo studies

ContextDehydroandrographolide succinate (DAS) is mainly used in the clinical treatment of various infectious diseases. Its potential effects on platelet aggregation and blood coagulation systems have not been reported systematically.ObjectiveTo explore whether DAS exerts an antithrombotic effect and its internal mechanism.Materials and methodsHuman blood samples and Sprague-Dawley (SD) rats divided into control, aspirin (30 mg/kg), and DAS groups (200, 400 and 600 mg/kg) were used to measure the platelet aggregation rate, coagulation function, coagulation factor activity, and contents of thromboxane B₂ (TXB₂) and 6-keto-prostaglandin F_1α (6-keto-PGF_1α). The histopathology of the SD rat gastric mucosa was also observed. All rats were administered intragastric or intraperitoneal injections once a day for 3 consecutive days.ResultsCompared to control group, DAS significantly inhibited the platelet aggregation rate (ED₅₀ = 386.9 mg/kg) by decreasing TXB₂ levels (1531.95 ± 649.90 pg/mL to 511.08 ± 411.82 pg/mL) and activating antithrombin III (AT-III) (103.22 ± 16.22% to 146.46 ± 8.96%) (p < 0.05). In addition, DAS significantly enhanced the coagulation factors FV (304.12 ± 79.65% to 443.44 ± 75.04%), FVII (324.19 ± 48.03% to 790.66 ± 225.56%), FVIII (524.79 ± 115.47% to 679.92 ± 143.34%), FX (34.90 ± 7.40% to 102.76 ± 29.41%) and FXI (38.12 ± 10.33% to 65.47 ± 34.08%), increased the content of Fg (2.18 ± 0.39 to 3.61 ± 0.37 g/L), shorten the PT (10.42 ± 0.44 to 9.22 ± 0.21 s), APTT (16.43 ± 1.4 to 14.07 ± 0.75 s) and TT time (37.04 ± 2.13 to 32.68 ± 1.29 s) (p < 0.05), while the aspirin group showed no such effect on these items but showed reduced activity of FII (89.21 ± 21.72% to 61.83 ± 8.95%) and FVIII (524.79 ± 115.47% to 306.60 ± 29.96%) (p < 0.05). Histopathological changes showed aspirin-induced gastric mucosa haemorrhage and the protective effect of DAS in the gastric mucosa.ConclusionsDAS is more suitable than aspirin in thromboprophylaxis treatment, which provides a reliable theoretical and experimental basis for its clinical application.     

Effect of Spray-Dried Particle Morphology on Mechanical and Flow Properties of Felodipine in PVP VA Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) are commonly used to enhance the oral absorption of drugs with solubility or dissolution rate limitations. Although the ASD formulation is typically constrained by physical stability and in vivo performance considerations, ASD particles can be engineered using the spray-drying process to influence mechanical and flow properties critical to tableting. Using the ASD formulation of 20% w/w felodipine dispersed in polyvinyl pyrrolidone vinyl acetate, spray-drying atomization and drying conditions were tuned to achieve 4 different powders with varying particle properties. The resulting particles ranged in volume moment mean diameter from 4 to 115 μm, bulk density from 0.05 to 0.38 g cm⁻³, and morphologies of intact, collapsed, and fractured hollow spheres. Powder flowability by shear cell ranged from poor to easy flowing, whereas mechanical property tests suggested all samples will produce strong tablets at reasonable solid fractions and compression pressures. In addition, Hiestand dynamic tableting indices showed excellent dynamic bonding for 3 powders, and low viscoelasticity with high brittleness for all powders. This work demonstrates the extent spray-dried ASD particle morphologies can be engineered to achieve desired powder flow and mechanical properties to mitigate downstream processing risks and increase process throughput.     

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.     

Soluplus®、PVP VA64为载体的氟苯尼考固体分散体的制备及体外评价

目的 采用新型载体材料Soluplus^®和PVP VA64制备氟苯尼考固体分散体,以增加其溶解度及体外溶出度。方法 应用溶解度参数法初步预测药物与载体材料的相容性,进一步采用溶剂蒸发法制备氟苯尼考-Soluplus^®和氟苯尼考-PVP VA64固体分散体,并采用差示扫描量热法（DSC）、X-射线粉末衍射法（XPRD）、傅里叶变换红外光谱法（FTIR）对所得固体分散体进行表征,且与PVP K30进行比较。以溶解度和体外溶出度为评价指标,对不同载体制备的氟苯尼考固体分散体进行比较。结果 DSC、XPRD和FTIR结果表明,不同高分子材料制得的氟苯尼考固体分散体中药物均呈无定型状态;几种载体材料均能增加氟苯尼考的溶解度及溶出速率,增溶效果为PVP VA64>PVP K30>Soluplus^®,其中PVP VA64固体分散体的溶解度增加最为显著,25℃在标准硬水、自来水、纯化水中的溶解度约为原料药的3倍,且自来水中5 min时累积溶出率可达88.23%,为氟苯尼考原料药的20.56倍。结论 采用溶剂蒸发法制备氟苯尼考-PVP VA64固体分散体可以显著提高药物的溶解度及体外溶出度。