Degradation of hydroxypropylcellulose by Rhizomucor: effects on release from theophylline-hydroxypropylcellulose tablets

The stability of several varieties of hydroxypropylcellulose was monitored during 3 years of storage (1) under the conditions recommended by manufacturers and official pharmacopoeias (simple storage in closed containers) and (2) at zero relative humidity. After 1 year, severe degradation of the varieties with lower initial pH and particle size stored at ambient relative humidity was shown by changes in their molecular weight and in the pH and apparent viscosity of 2% aqueous dispersions. Microbiological analyses showed the observed degradation to be attributable to the action of fungi of the genus Rhizomucor. The changes in apparent viscosity significantly affected the release of theophylline from direct compression tablets formulated with the degraded excipients.     

Improvement of flow and bulk density of pharmaceutical powders using surface modification

Improvement in flow and bulk density, the two most important properties that determine the ease with which pharmaceutical powders can be handled, stored and processed, is done through surface modification. A limited design of experiment was conducted to establish a standardized dry coating procedure that limits the extent of powder attrition, while providing the most consistent improvement in angle of repose (AOR). The magnetically assisted impaction coating (MAIC) was considered as a model dry-coater for pharmaceutical powders; ibuprofen, acetaminophen, and ascorbic acid. Dry coated drug powders were characterized by AOR, particle size as a function of dispersion pressure, particle size distribution, conditioned bulk density (CBD), Carr index (CI), flow function coefficient (FFC), cohesion coefficient using different instruments, including a shear cell in the Freeman FT4 powder rheometer, and Hansen flowability index. Substantial improvement was observed in all the measured properties after dry coating relative to the uncoated powders, such that each powder moved from a poorer to a better flow classification and showed improved dispersion. The material intrinsic property such as cohesion, plotted as a function of particle size, gave a trend similar to those of bulk flow properties, AOR and CI. Property improvement is also illustrated in a phase map of inverse cohesion (or FFC) as a function of bulk density, which also indicated a significant positive shift due to dry coating. It is hoped that such phase maps are useful in manufacturing decisions regarding the need for dry coating, which will allow moving from wet granulation to roller compaction or to direct compression based formulations.     

Influence of particle wall adhesion on particle electrification in mixers

In this work, particle electrification in the Turbula and horizontally oscillating mixers were investigated for adipic acid, microcrystalline cellulose (MCC), and glycine particles. MCC and glycine particles acquired positive electrostatic charges, while adipic acid particles attained negative charges in both mixers. Adipic acid (of sieved size larger than 500 microm), MCC, and glycine particles were monotonically charged to saturated values, and had negligible wall adhesion. On the contrary, the adipic acid particles, both unsieved and sieved but of smaller sieved size fraction, exhibited very different charging kinetics in the horizontally oscillating mixer. These adipic acid particles firstly acquired charges up to a maximum value, and then the charges slowly reduced to a lower saturated value with increasing mixing time. Furthermore, these particles were found to adhere to the inner wall of the mixer, and the adhesion increased with mixing time. Surface specific charge densities for adipic acid particles were estimated based on particle size distribution, and were found to increase with particle mean diameters under the conditions investigated. The results obtained from the current work suggested that electrostatic force enhanced particle-wall adhesion, and the adhered particles can have a significant impact on particle electrification.     

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations

Purpose

This study aims to investigate the influence of different storage humidity conditions on crystallization and aerosol performance of inhalable spray dried amorphous powder formulations (Ciprofloxacin hydrochloride as the model drug).

Methods

The spray dried samples were stored at 20%, 55% and 75% relative humidity (RH). Crystallinity was monitored by Powder X-ray diffraction (PXRD), and particle morphology was measured by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Aerosol performance was evaluated using a multi-stage liquid impinger (MSLI).

Results

PXRD diffractograms showed the spray dried Ciprofloxacin stored at 20% RH for three weeks were amorphous; whereas those stored at 55% RH and 75% RH started crystallizing after one hour. Fine particle fraction (FPF) of the particles was improved from 28% to 42% after storage at 55% RH for three days. Such improvement was attributed to the crystallization of amorphous powders, which led to increased particle roughness and reduced particulate contact area, as visualized by SEM and quantified by AFM. A linear relationship was observed between degree of crystallinity/crystallite size and FPF (R²?=?0.94 and R²?=?0.96, respectively). However, deterioration in aerosol performance was observed after storage at 75% RH due to formation of inter-particulate liquid/solid bridges, as confirmed by SEM.

Conclusions

This study provides a fundamental understanding in moisture-induced physical and aerosol instability of the spray dried powder formulations.

     

The effect of physical aging on the structural behavior of amorphous poly(vinylpyrrolidone) polymers

The purpose of the present study was to examine the physical ageing of amorphous polymers commonly applied in the pharmaceutical technology. Powder samples of polyvinylpyrrolidone were stored under different storage conditions (relative humidity, temperature). Positron annihilation lifetime spectroscopy (PALS) was applied for the analysis of the free volume changes of polymer samples as a function of the storage conditions. By the means of calculations on simplified model molecules it was determined that polymer chains and water molecules are able to form a hydrogen bound "network" under certain humidity conditions. Along with the ageing process the chemical changes of the examined polymers are interrelated in a dynamic and complex manner which can be tracked by the combination of SEM, ab initio calculations and positron lifetime measurements.     

The Effect of Relative Humidity on the Physical Properties of Two Melibiose Monohydrate batches with Differing Particle Size Distributions and Surface Properties

Melibiose monohydrate has shown promise when employed as a pharmaceutical excipient, but its physical properties have not been adequately characterized. Therefore, two different melibiose monohydrate batches were analyzed as received or after storage under different relative humidity (RH) atmospheres. The particle size distributions and specific surface areas of the two batches were shown to differ considerably, which also had an effect on their water sorption tendencies and on the intermolecular structure of melibiose after storage. The relatively large primary particles that were more abundant in one of the batches were shown to possess a porous surface structure, and water evaporation from them occurred in two phases when heated. Furthermore, storing the batch with smaller mean particle size under dry conditions affected the crystal structure and molecular vibrations of the sample more than in the case of the batch with larger mean particle size. It was concluded that the physical properties of melibiose monohydrate after storage at different RH atmospheres is largely governed by the primary particle size and porosity.     

Characterisation of the influence of micronisation on the crystallinity and physical stability of revatropate hydrobromide

Micronised particles of revatropate hydrobromide were observed to agglomerate when stored in uncontrolled conditions. Dynamic vapour sorption (DVS), isothermal microcalorimetry, microscopy and particle size measurement by laser diffraction have been used to study micronised revatropate hydrobromide. The rate and extent of agglomeration were dependent on the energy of the micronisation process, the sampling point for bulk within the mill and the humidity during storage. The agglomeration was attributed to the recrystallisation of disordered regions on the particles of revatropate hydrobromide generated during micronisation. This recrystallisation was assessed qualitatively and quantitatively, compared against spray-dried amorphous material, using DVS and isothermal microcalorimetry, respectively. A correlation was established between the energy of micronisation and the level of disorder within the micronised powder. A comparison of the DVS profiles of freshly prepared and aged micronised revatropate hydrobromide suggests an increased physical stability for the aged material.     

Influence of excipients in comilling on mitigating milling-induced amorphization or structural disorder of crystalline pharmaceutical actives

The feasibility of using excipients to suppress the amorphization or structural disorder of crystalline salbutamol sulphate (SS) during milling was investigated. SS was subjected to ball-milling in the presence of α-lactose monohydrate (LAC), adipic acid (AA), magnesium stearate (MgSt), or polyvinyl pyrrolidone (PVP). X-ray powder diffraction, dynamic vapor sorption (DVS), high sensitivity differential scanning calorimetry (HSDSC) were used to analyze the crystallinity of the milled mixtures. Comilling with crystalline excipients, LAC, AA, and MgSt proved effective in reducing the amorphization of SS. LAC, AA, or MgSt acting as seed crystals to induce recrystallization of amorphous SS formed by milling. During comilling, both SS and LAC turned predominantly amorphous after 45 min but transformed back to a highly crystalline state after 60 min. Amorphous content was below the detection limits of DVS (0.5%) and HSDSC (5%). Comilled and physical mixtures of SS and ALM were stored under normal and elevated humidity conditions. This was found to prevent subsequent changes in crystallinity and morphology of comilled SS:LAC as compared to significant changes in milled SS and physical mixture. These results demonstrate a promising application of comilling with crystalline excipients in mitigating milling induced amorphization of pharmaceutical actives. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2462–2474, 2010     

Effect of antioxidants and silicates on peroxides in povidone

Reactive peroxides in povidone often lead to degradation of oxidation-labile drugs. To reduce peroxide concentration in povidone, the roles of storage conditions, antioxidants, and silicates were investigated. Povidone alone and its physical mixtures with ascorbic acid, propyl gallate, sodium sulfite, butylated hydroxyanisole (BHA), or butylated hydroxytoluene (BHT) were stored at 25 °C and 40 °C, at 11%, 32%, and 50% relative humidity. In addition, povidone solution in methanol was equilibrated with silicates (silica gel and molecular sieves), followed by solvent evaporation to recover povidone powder. Peroxide concentrations in povidone were measured. The concentration of peroxides in povidone increased under very-low-humidity storage conditions. Among the antioxidants, ascorbic acid, propyl gallate, and sodium sulfite reduced the peroxide concentration in povidone, whereas BHA and BHT did not. Water solubility appeared to determine the effectiveness of antioxidants. Also, some silicates significantly reduced peroxide concentration in povidone without affecting its functionality as a tablet binder. Porosity of silicates was critical to their ability to reduce the peroxide concentration in povidone. A combination of these approaches can reduce the initial peroxide concentration in povidone and minimize peroxide growth under routine storage conditions.     

Light- and temperature-induced degradation of fumagillin

The antibiotic fumagillin with amebicidal and fungicidal effects isolated from Aspergillus fumigatus is the only presently known agent for the treatment of life threatening serious microsporidiosis occurring in patients with AIDS. Fumagillin and its degradation products were measured by HPLC at given time intervals after storage under defined conditions (temperature, relative humidity). Significant degradation took place even in samples stored in freezer; therefore fumagillin drug substance should be stored below -60 degrees C. Light also induced a degradation process in fumagillin, thus it is proposed to be stored and transported in brown glass.     

Long-term stability of quercetin nanocrystals prepared by different methods

Objectives This study aimed to examine the long‐term physical stability of quercetin nanocrystals produced by three methods. Methods Quercetin nanocrystals were prepared by high pressure homogenization, bead milling and cavi‐precipitation. The nanocrystals produced by these methods were compared for particle size, saturation solubility and dissolution of the drug particles, and were subjected to stability testing. Key findings The X‐ray diffraction study and microscopic pictures taken under polarized light indicated the crystalline nature of the nanocrystals produced by the three methods. As the crystalline state is relatively more stable than the amorphous state, a good physical stability was expected from the quercetin nanocrystals prepared. The high‐pressure homogenized and bead‐milled quercetin nanocrystals showed excellent physical stability when stored under refrigeration (4 ± 2°C) and at room temperature (25 ± 2°C) for 180 days. The dissolution properties were not significantly affected on storage at room temperature. However, increase in the storage temperature to 40 ± 2°C led to physical instability. On the other hand, the cavi‐precipitated quercetin nanocrystals exhibited a lower stability than the bead‐milled and homogenized formulations and did not show the optimum zeta potential values as well. In the case of cavi‐precipitated nanocrystals, recrystallization and agglomeration were responsible for the increasing particle size besides the Ostwald ripening phenomenon. The solvents used during cavi‐precipitation might have competed with the surfactant for hydration leading to a partial dehydration of the surfactant, which subsequently affected the stability of the quercetin nanocrystals. Conclusions High‐pressure homogenized and bead‐milled quercetin nanocrystals showed better physical stability than the cavi‐precipitated ones. Freeze drying immediately after nanocrystal production can help to prevent their agglomeration and thus improve physical stability.     

Accelerated stability study of sustained-release nifedipine tablets prepared with Gelucire

This paper describes an investigation of the chemical and physical stability of nifedipine sustained release dosage forms prepared with Gelucire® 53/10. Three formulations differing only in the applied tabletting force were stored for 6 months under four different controlled conditions of relative humidity (RH) and temperature (20°C/0% RH, 20°C/80% RH, 40°C/0% RH, 40°C/80%). It was found that nifedipine in the sustained release formulations was chemically stable against the effects of temperature and humidity. However, the variables, tabletting force, RH and storage time, exerted a significant influence on the dissolution behavior of nifedipine. The changes in dissolution behavior after storage under conditions of high humidity and temperature might be related to the formation of nifedipine microcrystals and to structural changes in the wax vehicle during storage. It is predicted that acceptable shelf-lives should result when moisture-resistant packaging is used for pharmaceutical formulations of this type.     

The angle of internal flow as an indicator of filling and drug release properties of capsule formulations

The cohesiveness of size fractions of acetylsalicylic acid and lactose alone and in various combinations has been determined by estimation of the rate of decrease in volume as a function of tamping under standard conditions. The cohesiveness was quantified in terms of empirically derived characteristic, the angle of internal flow phi. The value of phi was found to decrease with the particle size of acetylsalicylic acid, but not lactose, and was found to be dependent on the relative proportion and particle sizes of acetylsalicylic acid and lactose when blends of powder were studied. The value of the time for 50% of the drug content to be released from a hard gelatin capsule in an in-vitro dissolution test, T50, was found to decrease with decreasing values of omega for capsules containing acetylsalicylic acid alone. For capsules containing powder blends there was no consistent relationship between the value of T50 and phi.     

Influence of relative humidity on the mechanical and drug release properties of theophylline pellets coated with an acrylic polymer containing methylparaben as a non-traditional plasticizer.

The purpose of this study was to investigate the influence of relative humidity (RH) on the mechanical and dissolution properties of theophylline pellets coated with Eudragit((R)) RS 30 D/RL 30 D containing methylparaben (MP) as a non-traditional plasticizer. The coated beads were stored at 23 degrees C and at different relative humidities (0, 29, 51, 75 and 84% RH). The effect of storage conditions on the rate of drug release from coated beads was determined in pH 7.4 phosphate buffer solution. The mechanical properties, including tensile strength and Young's modulus, of individual beads were determined by a diametral compression method with a Chatillon((R)) tension/compression apparatus. The morphology of the intact and fractured beads was investigated using scanning electron microscopy (SEM). The moisture content of the polymeric films was determined using a Karl Fischer coulometric moisture analyzer. The results from the mechanical studies demonstrated that an increase in the relative humidity resulted in a decrease in the tensile strength and Young's modulus of the coated beads. SEM photographs showed that coated beads stored at 0% RH exhibited brittle fracture failure. The coated beads stored at 84% RH showed ductile behavior, which was attributed to the hydroplasticization effect on the acrylic polymer due to the uptake of moisture. The moisture content in the films was also shown to influence the rate of drug release from Eudragit((R)) RS 30 D/RL 30 D coated beads containing MP as the plasticizer. The change in release profiles could be minimized when the relative humidity was reduced to zero. The dissolution rate of theophylline from the coated beads decreased when stored at high relative humidities. This trend was reversed when the coated beads that were stored at 84% RH for 5 weeks, were then equilibrated at 0% RH.     

环境湿度对硫酸氢氯吡格雷片溶出度的影响

目的 考察2种处方的硫酸氢氯吡格雷片在(75±5)%相对湿度(relative humidity,RH)条件下放置时长对溶出速率的影响,为药物溶出曲线检测异常数据的调查提供参考。方法 将硫酸氢氯吡格雷片处方1和处方2的样品装入密闭的样品盒中,置于饱和氯化钠溶液模拟的75%RH的环境中放置1,2,3 h后检测溶出曲线和水分,并与未经吸湿样品的溶出曲线进行非模型依赖相似因子比较。结果 处方1的样品在(75±5)%RH下放置2 h后即与0 h不相似,而处方2的样品放置4 h后仍然相似。处方1制剂在3 h内水分增长比处方2制剂快,并且在5 h内持续增长,而处方2制剂在2 h后水分增长即变缓。结论 处方1中的崩解剂比处方2多了交联聚维酮,含有交联聚维酮的处方对环境的湿度变化比较敏感,因此对于此类制剂不管是在保存还是检测都应该考虑环境湿度的影响。     

Preparation and in-vitro evaluation of sustained-release metoclopramide hydrochloride microspheres

Abstract

Sustained-release metoclopramide microspheres were successfully prepared using cellulose propionate polymer at 1:2 drug to polymer ratio employing solvent evaporation technique and using acetone as the polymer solvent. The prepared microspheres at three stirring speeds were characterized with regard to their drug content, particle size distribution, surface topography using SEM and their release profiles at two different pHs at 37°C. The surface of all samples was smooth with very few irregular elevations or depressions. The average particle size decreases as the rotational speed increases and was found to be 1320, 774 and 345 μm at 600, 900 and 1200rpm, respectively. The average % drug entrapped was found to be 90.5, 100.1 and 60.0% at 600, 900 and 1200 rpm, respectively. Small differences in the release rate were observed due to different rotation speeds with an apparent lower dissolution for batches produced at 1200 rpm probably due to the properties of the coat. The effect of storage under accelerated conditions for 10 weeks on the release characteristics of these microspheres was also studied. The release properties of the microspheres did not change after storing them at 40°C/80% relative humidity for 10 weeks.     

Release characteristics of freeze-dried eugenol encapsulated with β-cyclodextrin by molecular inclusion method

The study investigated the thermo-physical properties of eugenol encapsulated with β-cyclodextrin (β-CD) by molecular inclusion and eugenol release characteristics at various relative humidities and storage temperatures. Particle size, Zeta-potential, thermal transition and morphology of β-CD-Eugenol complex after freeze-drying measured using Nanosizer®, differential scanning calorimeter (DSC) and transmission electron microscopy (TEM), respectively. The particle size, Zeta-potential and inclusion efficiency of encapsulated eugenol presented ～340 nm, ?34.5 mV and 91.7% after freeze-drying, respectively. The relationship between retention rate of eugenol and time during release was described by a mathematical model of Avrami equation. In these events, the parameter of release mechanism and the release rate constant were rapidly elevated with increasing relative humidity and storage temperature. Furthermore, the Arrhenius activation energy for the release of eugenol decreases with increasing relative humidity and storage temperature.     

棕榈酸帕利哌酮微晶的制备与质量评价

棕榈酸帕利哌酮为难溶性药物,通常采用研磨法降低药物粒径从而提高药物的溶出速度。本试验将含有合适稳定剂的油水两相碰撞后经微射流高压均质法制备棕榈酸帕利哌酮混悬液;再经冷冻干燥技术制成棕榈酸帕利哌酮微晶,以提高稳定性。通过单因素试验和正交设计优化得到的最优处方和工艺为:联用大豆磷脂和聚乙烯醇为稳定剂,大豆磷脂、聚乙烯醇与主药的质量比分别为1∶13和1∶9.75;油水相体积比为1∶2;均质压力为137.90 MPa。测得该混悬液冻干前的d(0.5)在4.5 μm以内;室温放置7 d期间粒径基本保持稳定。选择甘露醇为冻干保护剂,制得的冻干粉末在加速试验(40 ℃、相对湿度75%)条件下放置3个月期间粒径及分布基本保持稳定,表明该制备工艺稳定可行。体外释放试验结果表明,将该药物制成微晶后,释放度得到显著改善。     

An investigation into water interactions with amorphous and milled salbutamol sulphate: the development of predictive models for uptake and recrystallization

An investigation into the effect of water uptake on the glass transition of spray dried and milled salbutamol sulphate has been performed, with a particular view to exploring how the water uptake, T(g) value and recrystallization behaviour correlate. Samples of milled and spray dried drug were stored under controlled humidity conditions and the T(g) measured as a function of time. The T(g) was measured using modulated temperature differential scanning calorimetry (MTDSC) while the water content was measured using thermogravimetric analysis (TGA). A correlation was found between time of storage, water content and T(g) in that the samples showed time dependent equilibration with the storage environment (either gaining or losing water depending on the RH). The relationship between water content and stability, based on the concept of T(g) lowering, was modelled using the semi-empirical approach of Royall et al. (1999) as well as a derivation of the Kwei equation which allowed the interaction between the water and substrate to be accounted for. A method for predicting stability based on two simple DSC runs is proposed. In addition, we discuss the observation of a double glass transition for the spray dried samples.     

Following the surface response of caffeine cocrystals to controlled humidity storage by atomic force microscopy

Active pharmaceutical ingredient (API) stability in solid state tablet formulation is frequently a function of the relative humidity (RH) environment in which the drug is stored. Caffeine is one such problematic API. Previously reported caffeine cocrystals, however, were found to offer increased resistance to caffeine hydrate formation. Here we report on the use of atomic force microscopy (AFM) to image the surface of two caffeine cocrystal systems to look for differences between the surface and bulk response of the cocrystal to storage in controlled humidity environments. Bulk responses have previously been assessed by powder X-ray diffraction. With AFM, pinning sites were identified at step edges on caffeine/oxalic acid, with these sites leading to non-uniform step movement on going from ambient to 0% RH. At RH >75%, areas of fresh crystal growth were seen on the cocrystal surface. In the case of caffeine/malonic acid the cocrystals were observed to absorb water anisotropically after storage at 75% RH for 2 days, affecting the surface topography of the cocrystal. These results show that AFM expands on the data gathered by bulk analytical techniques, such as powder X-ray diffraction, by providing localised surface information. This surface information may be important for better predicting API stability in isolation and at a solid state API–excipient interface.