Evaluation of solid state form of troglitazone by solid state NMR spectroscopy

The solid state forms of troglitazone drug substance and diastereomers were characterized using solid state nuclear magnetic resonance (SSNMR) spectroscopic method. The SSNMR spectroscopy could distinguish the hydrated and the non-hydrated RR/SS forms more clearly than powder X-ray diffractometry (PXRD). The SSNMR result supported that troglitazone drug substance consists of diastereomers as a simple physical mixture. SSNMR spectroscopy was also able to characterize the solid state forms of troglitazone in tablets while PXRD was unable to because of interference from the pharmaceutical additives. Troglitazone was proved to exist in amorphous form in tablets, and keep its solid state form amorphous against heat and humidity. SSNMR spectroscopy thus provides very important information for the development of the pharmaceutical formulation of troglitazone.     

Dissolution improvement of four poorly water soluble drugs by cogrinding with commonly used excipients.

The rate of the dissolution of four poorly soluble drugs (EMD 57033, albendazole, danazol and felodipine) was improved by cogrinding them with various excipients (lactose monohydrate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and sodium lauryl sulphate) using a jet-milling technique. Solid state characterization studies by X-ray diffraction and differential scanning calorimetry verified the maintenance of the crystalline state of the active substances after milling. In vitro dissolution of the coground mixtures in biorelevant media was much faster than from micronised drug in the corresponding physical mixtures for all four compounds. Supersaturated solutions were generated in some cases (EMD 50733 and felodipine), but this phenomenon appeared to be drug- and excipient-specific. Cogrinding with lactose monohydrate resulted in fast dissolution with unstable supersaturation for EMD 57033. Cogrinding the same drug with PVP or HPMC produced a more sustained supersaturation. SLS accelerated the dissolution of EMD 50733 but inhibited supersaturation. The results suggest that the cogrinding with selected excipients is a powerful tool to accelerate the dissolution of poorly soluble drugs without converting the drug to the amorphous form or changing the particle size.     

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 degrees 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.     

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.     

Review: Use of Thermal, Diffraction, and Vibrational Analytical Methods to Determine Mechanisms of Solid Dispersion Stability

Formulations such as amorphous dispersions have been proposed to counter the ever present need to make drug products sufficiently soluble. However, a major concern with amorphous pharmaceuticals is physical instability, where the higher free-energy form will spontaneously revert to the more stable (and less soluble) crystalline form. Proposed mechanisms of amorphous pharmaceutical stabilization via solid dispersions are presented, as well as the analytical methods used to understand or monitor physical stability. This work focuses on differential scanning calorimetry, Raman and infrared spectroscopy, and powder X-ray diffraction, based on the general accessibility of these methods and abundant references in the pharmaceutical literature.     

Structure and physical stability of hydrates and thermotropic mesophase of calcium benzoate

The aim of this study is to investigate the hydration and the dehydration processes of calcium benzoate hydrates (trihydrate and monohydrate), thermotropic mesophases (dehydrated mesophase and lyophilized mesophase) and amorphous state, and the influence of their molecular order on those processes. X-ray analysis revealed that trihydrate has a planar structure composed of two types of planes-one from benzoic acid, water, and calcium ion and another from benzoic acid and water-and that both planes are linked by three water molecules. It was found that calcium benzoate was able to exist as thermotropic mesophases by dehydration of trihydrate and lyophilization. These mesophases were characterized by polarizing-light microscopy (PLM), X-ray powder diffraction (XRPD), differential thermal analysis (DTA), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). Both mesophases prepared by two procedures showed some similar physical properties, but lyophilized mesophase seemed to have molecular structure with higher order than dehydrated mesophase. The mesophases exhibited different hydration behavior. The dehydrated mesophase showed a stepwise rehydration process where it became monohydrate first and then trihydrate. The lyophilized mesophase became trihydrate without appearance of monohydrate. An amorphous form could also be prepared and it rehydrated first to the monohydrate and then trihydrate. The results suggest that the more disordered dehydrated mesophase and amorphous state change to monohydrate whereas the more ordered lyophilized mesophase cannot change to monohydrate but only to trihydrate.     

联苯双酯制剂的物理分散状态及体外释放度

用X-射线衍射法,考察不同载体制备的固体分散体系中联笨双酯的物理分散状态,聚乙二醇6000(PEG 6000)固体分散系为有限互溶固体溶液,聚乙烯吡咯烷酮(PVP)共沉淀物为无定形粉末,脲共熔物为简单低共熔混合物,热分析研究亦证实PEG 6000固体分散物较其相应比例的物理混合物及片剂有更高的分散度。比较两种联苯双酯片剂与滴丸的体外释放度,两种片剂的释放度参数td值分别为37和178min,滴丸未包衣者为11min,包衣者为26.in。由此可知物理分散状态是影响释放速度的主要因素。     

联苯双酯制剂的物理分散状态及体外释放度

用X-射线衍射法,考察不同载体制备的固体分散体系中联笨双酯的物理分散状态,聚乙二醇6000(PEG 6000)固体分散系为有限互溶固体溶液,聚乙烯吡咯烷酮(PVP)共沉淀物为无定形粉末,脲共熔物为简单低共熔混合物,热分析研究亦证实PEG 6000固体分散物较其相应比例的物理混合物及片剂有更高的分散度。比较两种联苯双酯片剂与滴丸的体外释放度,两种片剂的释放度参数td值分别为37和178min,滴丸未包衣者为11min,包衣者为26.in。由此可知物理分散状态是影响释放速度的主要因素。     

Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media

Controlled precipitation produced aqueous nanoparticle suspensions of a poorly water soluble drug, itraconazole (ITZ), in an amorphous state, despite unusually high potencies (drug weight/total weight) of up to 94%. Adsorption of the amphiphilic stabilizer hydroxypropylmethylcellulose (HPMC) at the particle-aqueous solution interface arrested particle growth, producing surface areas from 13 to 51 m(2)/g. Dissolution of the particles in acidic media yielded high plateau levels in supersaturation up to 90 times the equilibrium solubility. The degree of supersaturation increased with particle curvature, as characterized by the surface area and described qualitatively by the Kelvin equation. A thermodynamic analysis indicated HPMC maintained amorphous ITZ in the solid phase with a fugacity 90 times the crystalline value, while it did not influence the fugacity of ITZ in the aqueous phase. High surface areas led to more rapid and levels of supersaturation higher than those seen for low-surface area solid dispersions, which undergo crystallization during slow dissolution. The rapid generation of high levels of supersaturation with potent amorphous nanoparticles, containing small amounts of stabilizers oriented at the particle surface, offers new opportunities for improving bioavailability of poorly water soluble drugs.     

Physical characterization of solid iopanoic acid forms.

Three solid forms of iopanoic acid were characterized by X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, thermal microscopy, IR spectroscopy, and dissolution studies. X-ray analysis demonstrated that two solid forms were crystalline and that the third was amorphous. The amorphous form had been reported previously as crystalline. Enthalpies and entropies of transition were calculated using differential scanning calorimetry. A fourth form, a benzene solvate, also was isolated but proved to be too unstable at room temperature to permit conclusive characterization. The amorphous form demonstrated a 10-fold greater intrinsic dissolution rate than the commercially available form (Form I). Form II's intrinsic dissolution rate was 1.5 times greater than that of Form I. In powder dissolution studies, the peak solubilities of the different forms followed the same rank order as their intrinsic dissolution rates. Form II was relatively stable in aqueous saturated solutions, but the amorphous form was rapidly converted to Form I under similar conditions.     

电纺制备酮洛芬纳米纤维状固体分散体

以水难溶性药物酮洛芬为模型、聚乙烯吡咯烷酮为成纤基材,使用高压静电纺丝技术制各固体分散体.场扫描电镜观察到纳米纤维状固体分散体具有连续三维立体网状结构特征,X-射线衍射和差示扫描量热分析结果表明,药物以无定形或分子状态高度分散于聚合物基材中,傅里叶红外光谱分析结果证明,酮洛芬与聚乙烯吡咯烷酮之间能通过氢键相互作用.体外溶出结果表明,所制备的纳米纤维状固体分散体中酮洛芬能在30s内释放完全.     

Stable and Fast-Dissolving Amorphous Drug Composites Preparation via Impregnation of Neusilin® UFL2

A promising approach to increase the aqueous solubility, hence the bioavailability, of poorly water-soluble drugs is to convert them into their amorphous state through impregnation into mesoporous silica. Unfortunately, mesoporous silica is not yet available in bulk quantities due to high manufacturing costs. In this work, feasibility of using a commercially available cost-effective mesoporous fine grade Neusilin^® UFL2 to prepare amorphous drug composites of 2 model poorly soluble drugs, fenofibrate and itraconazole, is established. In contrast to fluidized-bed spray-impregnation, only mixing and drying steps are required. Complimentary assessment using X-ray powder diffraction, differential scanning calorimetry, and Raman spectroscopy confirmed drug within the composites to be amorphous at as high as 30% drug loading both after formation and after 3 months of storage at 40°C and 75% relative humidity. Amorphous drug recrystallization was completely suppressed due to the confinement effect due to the Neusilin^®. The amorphous drug composites resulted in higher apparent solubility and faster dissolution rate of the model drugs as compared to their crystalline counterpart, confirmed by United States Pharmacopeia II dissolution and ultraviolet surface dissolution imaging. Overall, stable, high drug-loaded fast-dissolving amorphous drug composites preparation using Neusilin^® UFL2 is demonstrated as a promising approach to enhance solubility of poorly soluble drugs.     

Stability of nilvadipine solid dispersion tablet with non-packaging condition

Nilvadipine (NIL) solid-dispersion tablets were stored counter to packaging instructions by exposing them to 40 degrees C, 25 degrees C, 75% relative humidity, and light. The dissolution, stability assay, and tablet properties (weight, thickness and hardness) were then examined. NIL dissolved more than 85% after all storage periods with exposure to high temperature and humidity. Powder X-ray diffraction analysis indicated that NIL was present in an amorphous state as in the initial state. The stability assay of NIL showed that it was more than 99% stable during all storage periods when exposed to temperature, humidity, and light, indicating good stability. Tablet properties were influenced by humidity more than by temperature, and the hardness of tablets decreased with time to 42.9 N after storage of 3 months.     

A study of the differences between two amorphous spray-dried samples of cefditoren pivoxil which exhibited different physical stabilities

The objective of this study was to investigate the reasons for the difference in physical stability of two amorphous cefditoren pivoxil samples that had been prepared using spray drying at inlet-air temperatures of 40 degrees C (SD-A) and 100 degrees C (SD-B). The two samples appeared amorphous by powder X-ray diffraction and had indistinguishable glass transition temperatures. Despite the fact that glass transition is often regarded as an indicator of the stability of amorphous forms, crystallisation was observed for SD-A, but not for SD-B, during storage at 60 degrees C and 81% relative humidity (RH). Gravimetric water sorption data demonstrated very similar water sorption until high RH values, at which point SD-A sorbed more water than did SD-B. The values of the dispersive, acidic (K(A)) and basic (K(D)) components of surface energy of the spray-dried samples were obtained using inverse gas chromatography (IGC), in the dry state and after equilibration with different RH environments. The data showed that the two amorphous samples had different surface properties and that the effect of sorbed water on these samples was also different. It is concluded that the two samples did not have long-range order, but had differences in the orientation of molecules at the surface, which were significant enough to alter the stability when the samples were stressed with water vapour and high temperature storage. IGC proved a valuable tool with which to study changes in the surface properties of amorphous materials.     

The physicochemical properties of digoxin

In a study of variations in the physicochemical properties of digoxin powder from several commercial sources, recrystallizations of digoxin were performed under several conditions. Polymorphs were not obtained whereas a pure amorphous form was formed under certain conditions. The amorphous form was more soluble and more stable under compression than was the crystalline form; nevertheless in contact with water it crystallized quickly. Traces of the crystalline form reduced the dissolution rate and stability of the amorphous form. Variations in the thermal behaviour of commercial samples can be explained by the presence of variable proportions of the amorphous form and also by thermal decomposition that varies from one sample to another and generally occurs at 160 degrees C and above.     

Pair distribution function X-ray analysis explains dissolution characteristics of felodipine melt extrusion products

Solid solutions of felodipine with EUDRAGIT E and EUDRAGIT E/NE were shown to dramatically increase the dissolution rate of felodipine in biorelevant media. Of the two polymer systems, extrudates containing 5% EUDRAGIT NE showed a faster dissolution rate and less recrystallization (no precipitation within 2 h). Although differential scanning calorimetry (DSC) and conventional X-ray powder diffraction (XRPD) were able to verify the amorphous state of the drug after melt extrusion, it was not possible to differentiate the two extrudate compositions further with these methods. We then applied pair distribution function (PDF) analysis to investigate extrudates. It was possible to more closely characterize the solid state of the amorphous extrudates in terms of local structural order: PDF analysis revealed that addition of minor amounts of EUDRAGIT NE to the main component EUDRAGIT E during extrusion changed the local structure of EUDRAGIT E in a nonadditive way. We conclude that local ordering can be important to the release characteristics of extrudates, even when the components are present in the amorphous state.     

Non-crystallinity determination by thermal analysis of freeze-dried cephalothin sodium

Cephalothin sodium (CET-Na) prepared according to the conventional freeze-drying methods is known to easily develop color during storage. Since amorphous CET-Na has been reported to be markedly unstable, the color development is thought to be due to the presence of traces of CET-Na in an amorphous state observed with scanning electron microscopy. Quantitation by use of the powder X-ray diffractometry of such traces of amorphous CET-Na has proved to be of little use. Thermogravimetry (TG) and differential scanning calorimetry (DSC) have demonstrated that the freeze-dried CET-Na by the conventional methods contains three types of CET-Na: amorphous (unstable phase), quasi-crystalline (metastable phase) and crystalline (stable phase). Pyrolysis initiation temperatures of these three types of CET-Na have been demonstrated to become higher in this order. A new parameter for the evaluation of non-crystallinity of CET-Na has been introduced, in which the ratio is calculated from the data of the total weight loss observed through the pyrolysis of both amorphous and quasi-crystalline CET-Na against the total weight loss of all components during the pyrolysis of sample specimen. The ratio thus calculated is defined as "non-crystallinity". This new parameter has successfully been introduced to establish a good correlation to the degree of increasing color intensity with aging of freeze-dried CET-Na.     

Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties

The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f(2)<50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ.     

Studies on drug-milk freeze-dried formulations. I: Bioavailability of sulfamethizole and dicumarol formulations

In this study, solid dispersion formulations of dicumarol (3,3'-methylenebis[4-hydroxycoumarin]) and sulfamethizole (N'-(5-methyl-1,3, 4-thiadiazol-2-yl)sulfanilamide) in defatted milk were prepared by freeze-drying. X-ray crystallographic data showed that both drugs were dispersed in the formulations in an amorphous state. Bioequivalency comparisons between freeze-dried formulations, after regeneration with water, and control capsules containing the pure drug substances were studied in four male volunteers. Determination of the plasma dicumarol levels indicated superiority of the dicumarol-milk formulation. Statistically significant differences were found between area under the curve, maximum plasma concentration, and apparent elimination rates. Analysis of the urine sulfamethizole data revealed that the two formulations exhibit statistically equivalent rates and extents of excretion of unchanged sulfamethizole. The binding of both drugs to casein and their solubility in the presence of casein were measured in vitro. The presence of casein caused an increase in the solubility of dicumarol, while it had no effect on the solubility of sulfamethizole. Normal protein binding cannot be responsible for the effects noted. Extrapolation of the in vitro data to the in vivo situation was attempted. Drug-milk freeze-dried formulations are promising for the enhancement of the bioavailability of sparingly water soluble drugs.     

Polymorphic form of piroxicam influences the performance of amorphous material prepared by ball-milling

The objective of this study was to investigate the influence of the starting solid state form of piroxicam (anhydrate form I: PRXAH I vs form II: PRXAH II) on the properties of the resulting amorphous material. The second objective was to obtain further insight into the impact of critical factors like thermal stress, dissolution medium and storage conditions on the thermal behavior, solid state transformations and physical stability of amorphous materials. For analysis differential scanning calorimetry (DSC), Raman spectroscopy and X-ray powder diffractometry (XRPD) were used. Pair-wise distribution function (PDF) analysis of the XRPD data was performed. PDF analysis indicated that the recrystallization behavior of amorphous samples was influenced by the amount of residual order in the samples. The recrystallization behavior of amorphous samples prepared from PRXAH I showed similarity to the starting material, whereas the recrystallization behavior of amorphous samples prepared from PRXAH II resembled to that of the PRX form III (PRXAH III). Multivariate data analysis (MVDA) helped to identify that the influence of storage time and temperature was more pronounced in the case of amorphous PRX prepared from PRXAH I. Furthermore, the wet slurry experiments with amorphous materials revealed the recrystallization of amorphous material as PRXMH in the biorelevant medium.