酮洛芬-聚乙烯吡咯烷酮固体分散物的制备及其体外溶出度的研究

目的提高难溶性药物酮洛芬体外溶出速度。方法以聚乙烯吡咯烷酮(PVPK30)为载体,制备药物与载体不同比例的固体分散物及物理混合物,采用X射线衍射和红外吸收方法,比较二者及药物的结晶形态,并进行体外药物溶出度的测定。结果固体分散物体外溶出速率明显高于物理混合物及酮洛芬原料的体外溶出速度,且随载体比例增加而增大。固体分散物的X射线衍射及红外吸收图谱确定了酮洛芬以无定形态分散在载体中,放置6个月后,固体分散物X射线衍射图谱没有明显变化。结论药物与载体以合适比例制备的固体分散物可以明显提高药物体外溶出速度。     

The characterization and dissolution performances of spray dried solid dispersion of ketoprofen in hydrophilic carriers

Solid dispersion is one of the most promising strategies to improve oral bioavailability of poorly soluble API. However, there are inconsistent dissolution performances of solid dispersion reported which entails further investigation. In this study, solid dispersions of ketoprofen in three hydrophilic carriers, i.e. PVP K30, PVPVA 6:4 and PVA were prepared and characterized. Physical characterization of the physical mixture of ketoprofen and carriers shows certain extent of amorphization of the API. This result is coinciding to evaluation of drug–polymer interaction using ATR-FTIR whereby higher amorphization was seen in samples with higher drug–polymer interaction. XRPD scanning confirms that fully amorphous solid dispersion was obtained for SD KTP PVP K30 and PVPVA system whereas partially crystalline system was obtained for SD KTP PVA. Interestingly, dissolution profiles of the solid dispersion had shown that degree of amorphization of KTP was not directly proportional to the dissolution rate enhancement of the solid dispersion system. Thus, it is concluded that complete amorphization does not guarantee dissolution enhancement of an amorphous solid dispersion system.     

Evaluation of molecular pharmaceutical and in‐vivo properties of spray‐dried isolated andrographolide—PVP

Objectives Andrographolide, a natural lipophilic molecule, has a wide range of pharmacological actions. However, due to low aqueous solubility, it has low oral bioavailability. The purpose of the study was to increase the solubility and dissolution rate of isolated andrographolide by formulating its solid dispersion. Method Solid dispersions were obtained by a spray‐drying technique using different ratios of drug to polyvinylpyrrolidine (PVP K‐30). Solid dispersions in compression with isolated drug and corresponding physical mixtures were characterized for various molecular pharmaceutical properties and subjected to stability study for up to 3 months. Key findings A five‐fold increase in saturation solubility of andrographolide with higher values of Q_5min (cumulative percentage release in 5 min) and lower values of t_75% (time required for 75% w/w drug release) for solid dispersion was observed in different dissolution mediums. This was attributed to the formation of amorphous nature and intermolecular hydrogen bonding between drug and PVP K‐30. The stability study showed there to be no significant change in molecular pharmaceutical properties and dissolution profile over the period of 3 months. Moreover, the in‐vivo study in Wistar albino rats also justified improvement in the therapeutic efficacy of andrographolide after solid dispersion. Conclusions This study demonstrates the utility of solid dispersion to improve primary and secondary pharmaceutical properties of andrographolide using PVP K‐30 as a carrier.     

Physicochemical Characterization and Dissolution Study of Solid Dispersions of Lovastatin with Polyethylene Glycol 4000 and Polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to‐carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile of Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods

This study compares the physicochemical properties of carbamazepine (CBZ) solid dispersions prepared by either a conventional solvent evaporation versus a supercritical fluid process. Solid dispersions of carbamazepine in polyvinylpyrrolidone (PVP) K30 with either Gelucire 44/14 or Vitamin E TPGS, NF (d-alpha-tocopheryl polyethylene glycol 1000 succinate) were prepared and characterized by intrinsic dissolution, differential scanning calorimetry, powder X-ray diffraction and Fourier transform infrared spectroscopy. CBZ/PVP K30 and CBZ/PVP K30/TPGS solid dispersions showed increased dissolution rate. The best intrinsic dissolution rate (IDR) was obtained for supercritically processed CBZ/PVP K30 that was four-fold higher than pure CBZ. Thermograms of various solid dispersions did not show the melting peak of CBZ, indicating that CBZ was in amorphous form inside the carrier system. This was further confirmed by X-ray diffraction studies. Infrared spectroscopic studies showed interaction between CBZ and PVP K30 in solid dispersions. The amorphous state of CBZ coupled with presence of interaction between drug and PVP K30 suggests fewer, if any, stability problems. Because the supercritical-based process produced solid dispersions with IDR better than conventional solid dispersions augmented with amphiphilic carriers, stability issues associated with lipid carriers do not apply, which, in turn, implies easier scale up under current Good Manufacturing Practice for this technique.     

Physicochemical characterization and dissolution study of solid dispersions of Lovastatin with polyethylene glycol 4000 and polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to-carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

格列喹酮固体分散体的制备及溶出度测定

目的:制备格列喹酮固体分散体并考察其体外溶出性。方法:以聚乙烯吡咯烷酮K30(PVP)、聚乙二醇6000(PEG)为载体,溶剂熔融法和溶剂法制备格列喹酮固体分散体,并与原料药比较体外溶出度。结果:载体比例越大,药物溶出愈快。载体为PVP所制固体分散体的体外溶出行为总体优于载体为PEG者。格列喹酮-PVP固体分散体(1∶7)10min内体外溶出度达到70%以上,优于格列喹酮原料药。结论:成功制备了格列喹酮固体分散体。     

托伐普坦固体分散体的制备及体外溶出特性考察

目的 采用固体分散技术提高难溶性药物托伐普坦的体外溶出度。方法 选用聚维酮K_29/32为载体材料,以溶剂蒸发法制备托伐普坦固体分散体。采用差示扫描量热法(DSC)、X-射线粉末衍射法(XRPD)对所得固体分散体进行鉴定, 并进行溶解度、体外溶出实验。结果 固体分散体的DSC 图谱及X-射线粉末衍射确定了托伐普坦以无定形态分散在载体中, 体外溶解实验表明其溶出较原料药、物理混合物均有明显提高。结论 将托伐普坦与PVP K_29/32制成固体分散体,其分散状态发生了改变,溶出性能明显提高。     

马来酸罗格列酮固体分散体及其溶出速率

目的提高难溶性药物马来酸罗格列酮的体外溶出速率 ,满足脉冲制剂的设计要求。方法选用PVPK3 0为载体 ,用溶剂法制备了马来酸罗格列酮固体分散体 ,比较考察了原料药及其物理混合物和固体分散体的溶出差别 ,并通过红外光谱及X 射线粉末衍射对固体分散体进行了鉴定。结果体外溶出结果表明固体分散体能显著增加药物在水中及人工肠液中的溶出速率 ;红外光谱分析结果表明药物与载体之间没有发生化学反应 ;X 射线粉末衍射图谱表明药物以无定形状态分散于载体PVPK3 0中。结论固体分散体体外溶出速率的提高可以满足脉冲制剂的设计要求。     

难溶性药物水飞蓟宾固体分散体的制备及评价(英文)

采用溶剂法制备水飞蓟宾的PVP K30固体分散体以提高其溶解度和溶出速率;通过平衡溶解度、溶出速率、DSC和FTIR等方法验证和定性分析制备的固体分散体。水飞蓟宾的固体分散体与原料药及物理混合物相比,改善了药物的溶解度和溶出速率。DSC曲线显示水飞蓟宾的吸热峰消失,表明水飞蓟宾以无定形物分散于载体材料中;FTIR的研究结果表明水飞蓟宾的羟基和PVP K30的羰基发生了反应。固体分散技术可应用于难溶性药物以改善其体外溶出及进一步的体内吸收。     

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.     

Cefuroxime axetil solid dispersions prepared using solution enhanced dispersion by supercritical fluids

Cefuroxime axetil (CA) solid dispersions with HPMC 2910/PVP K-30 were prepared using solution enhanced dispersion by supercritical fluids (SEDS) in an effort to increase the dissolution rate of poorly water-soluble drugs. Their physicochemical properties in solid state were characterized by differential scanning calorimeter (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectrometry (FT-IR) and scanning electron microscopy. No endothermic and characteristic diffraction peaks corresponding to CA were observed for the solid dispersions in DSC and PXRD. FTIR analysis demonstrated the presence of intermolecular hydrogen bonds between CA and HPMC 2910/PVP K-30 in solid dispersions, resulting in the formation of amorphous or non-crystalline CA. Dissolution studies indicated that the dissolution rates were remarkably increased in solid dispersions compared with those in the physical mixture and drug alone. In conclusion, an amorphous or non-crystalline CA solid dispersion prepared using SEDS could be very useful for the formulation of solid dosage forms.     

Dissolution behaviour of nalidixic acid solid dispersions using water soluble dispersion carriers

The oral bioavailability of nalidixic acid (NA) is low due to its poor solubility and slow dissolution. Solid dispersions of NA containing varying concentrations of polyvinylpyrrolidone (PVP), beta-cyclodextrin (BCD) and sodium starch glycolate (SSG) were prepared by solvent evaporation technique in an attempt to improve dissolution rate of NA. Physical characterization of NA, physical mixtures (PM) and solid dispersions were investigated by a variety of analytical methods including scanning electron microscopy (SEM), infrared (IR) spectroscopy and powder X-ray diffraction (XRD). SEM was useful in the verification of possible nalidixic acid inclusion in the dispersion system by studying its surface and shape characteristics of different samples. IR analysis demonstrated no strong interaction between the drug and the carrier exists in the solid dispersions. The degree of crystallinity of nalidixic acid decreased and also differed with the dispersion systems of different carriers. Disolution studies indicated that the dissolution rate and percent dissolution efficiency (DE) were significantly increased in the solid dispersions compared with drug alone. The relative potency of the carriers to enhance the dissolution rate of nalidixic acid was in the order: BCD > PVP > SSG. The dissolution rate of the drug in the solid dispersions was faster when the ration of the drug to carrier was smaller. F-test suggests that first order model may be used for explaining the kinetics of drug release from all the solid dispersion systems.     

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.     

他克莫司固体分散体的制备及体外溶出度测定

目的:制备他克莫司固体分散体,提高他克莫司的体外溶出度。方法:以体外溶出度为指标,从泊洛沙姆188(Poloxamer188)、聚维酮K30(PVP K30)、羟丙甲纤维素(HPMCE3)、聚乙二醇6000(PEG6000)中筛选最优载体及其比例。并采用差示热量扫描(DSC)、红外光谱(FTIR)、电子扫描电镜(SEM)等进行物相表征。结果:4种不同载体制成的固体分散体均能增加他克莫司体外溶出度,通过比较优选出HPMCE3为最佳载体。物相鉴定表明,他克莫司大部分以无定型状态分散于HPMCE3中。结论:制备他克莫司-HPMCE3固体分散体可以明显提高其体外溶出度,且制备方法简单可行。     

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.     

Properties of solid dispersions of piroxicam in polyvinylpyrrolidone.

Solid dispersions of piroxicam were prepared with polyvinylpyrrolidone (PVP) K-17 PF and PVP K-90 by solvent method. The physical state and drug:PVP interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR analysis demonstrated the presence of intermolecular hydrogen bonding between piroxicam and PVP in solid dispersions. These interactions reflected the changes in crystalline structures of piroxicam. The amorphousness within the PVP moeity might be predicted in piroxicam dispersions by the disappearance of N-H or O-H peak of piroxicam. Dissolution studies indicated a significant increase in dissolution of piroxicam when dispersed in PVP. The better results were obtained with the lower molecular weight PVP K-17 than with higher molecular weight PVP K-90. The non-amorphous solid dispersions in PVP K-17 showed almost equally fast dissolution rates to amorphous dispersions in PVP K-90. The mechanism of dissolution of solid dispersion in PVP K-90 is predominantly diffusion-controlled due to the very high viscosity of PVP K-90. Dissolution was maximum with the amorphous solid dispersions containing drug:PVP K-17 1:5 and 1:6 which showed a 40-fold increase in dissolution in 5 min as compared with pure drug. Copyright     

卡维地洛固体分散体的制备及其体外溶出度的测定

目的 :制备卡维地洛固体分散体 ,提高其溶解度和溶速率。方法 :以聚乙烯吡咯烷酮 (PVP)、聚乙二醇 -6000(PEG -6000)为载体 ,以溶剂法和熔融法制备固体分散体 ,并进行体外溶出度研究。结果 :载体比例越大 ,药物溶出愈快 ;载体比例愈小 ,差异愈显著。载体为PVP所制固体分散体的体外溶出行为总体优于载体为PEG -6000的固体分散体。结论 :本试验所制卡维地洛固体分散体能加速体外溶出 ,提高生物利用度 ,可用于制备高效制剂     

Effect of physiochemical variables on phase solubility and dissolution behavior of indomethacin solid dispersion system

To study the influence of temperature and pH on solubility and dissolution behavior of indomethacin solid dispersions were prepared using several classes of hydrophilic carriers. Investigations on dissolution of indomethacin in binary system are reported earlier. However the phase solubility and dissolution behavior at different pH and temperature left void. The present investigation includes: phase solubility study at various pH; preparation of solid dispersion by solvent evaporation, melting and kneading method; characterization of various blends by dissolution study, and solid state studies to ensure interaction of drug with carrier. The binding between drug and carriers (PVP K30, βCD and PEG) was explained by thermodynamic parameters as calculated from phase solubility study. Indomethacin in association with PVP K30 showed very high apparent binding constant (Ka) and Gibb’s free energy change (?G) in comparison to other blends. The ternary system (drug:βCD:PVP K30, 1:5:1) showed better dissolution of about 80.97 and 99 % at pH 7.2 after 5 and 30 min respectively. At higher proportion of carrier (1:9) in binary solid dispersion of drug and PVP K30, drug dissolution was 96.23 and 97.85 % after 5 and 30 min respectively. This raised solubility of indomethacin would be helpful in designing a dosage form.     

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