A. P. Lötter

Characterization of the solubility and dissolution properties of several new rifampicin polymorphs, solvates, and hydrates.

Based on reports that tuberculosis is on the increase, this investigation into the physicochemical properties of rifampicin when recrystallized from various solvent systems was undertaken. Rifampicin is an essential component of the currently recommended regimen for treating tuberculosis, although relatively little is known about its solubility and dissolution behavior in relation to its solid-state properties. A rifampicin monohydrate, a rifampicin dihydrate, two amorphous forms, a 1:1 rifampicin:acetone solvate, and a 1:2 rifampicin:2-pyrrolidone solvate were isolated and characterized using spectral, thermal, and solubility measurements. The crystal forms were relatively unstable because except for the 2-pyrrolidone solvate, all the hydrated or solvated materials changed to amorphous forms after desolvation. Fourier transform infrared (FTIR) analysis confirmed the favorable three-dimensional organization of the pharmacophore to ensure antibacterial activity in all the crystal forms except the 2-pyrrolidone solvate. In the 2-pyrrolidone solvate, the strong IR signals of 2-pyrrolidone interfered with the vibrations of the ansa group. The 2-pyrrolidone solvate was the most soluble in phosphate buffer at pH 7.4. This solvate also had the highest solubility (1.58 mg/ml) and the fastest dissolution in water. In 0.1 M HCl, the dihydrate dissolved the quickest. A X-ray amorphous form (amorph II) was the least soluble and had the slowest dissolution rate because the powder was poorly wettable and very electrostatic.

Solubility and dissolution properties of generic rifampicin raw materials

Rifampicin shows polymorphism; therefore, it is necessary to select a suitable crystal form at an early stage of development to ensure optimum solubility and dissolution rates. This study was an investigation into the crystal properties of several rifampicin raw materials currently being used by manufacturers of generic rifampicin raw materials in South Africa. Powders were characterized by X-ray diffraction (XRD), infrared (IR) spectroscopy, and differential scanning calorimetry (DSC). The solubility in water and dissolution properties in water, buffer pH 7.4 and 0.1 M HCl, were also measured. The main difference between the powders was the amorphous content. XRD, IR, and DSC methods could detect the presence of amorphous rifampicin. In contrast to expectations, an increase in amorphous content significantly reduced the dissolution rate of the powders in water and buffer pH 7.4. This behavior was attributed to the electrostatic properties of the very fine particles in the amorphous powders. The results of this study showed that the physical properties of rifampicin raw materials varied not only among manufacturers, but also among batches from the same manufacturer.

Kinetic study of the solid-state photolytic degradation of two polymorphic forms of furosemide

Abstract In this paper some aspects influencing the solid-state photolytic degradation of two polymorphic forms of furosemide were investigated. Powder samples of the two polymorphic forms were exposed to prolonged UV irradiation, direct sunlight, in a normal and nitrogen atmosphere. The solid-state photolytic degradation of furosemide followed apparent first-order kinetics as described by a model consisting of nucleation and growth periods with eventual deceleration as it reached a maximum fraction degraded. Kinetic calculations revealed that this bilateral first-order degradation process was best described by a power law dependence (n = 2) of the fraction decomposed (α) on time (t) for the nucleation period and first-order kinetic degradation with an asymptote for the growth and deceleration period (Prout-Tompkins model). Overall, the rate constants during the nucleation period were significantly smaller than the growth period. Form I was photochemically more stable than form II, especially under a nitrogen atmosphere ( t 1 2 50 h ). The photolytic degradation of form II was not influenced by the presence of oxygen ( t 1 2 35 h under normal atmospheric conditions and 38 h in a nitrogen atmosphere). After exposure to sunlight 4-chloro-5-sulphamoylanthranilic acid (CSA) was found in significant concentrations in samples taken from both forms I and II. Photolytic degradation of furosemide form II led to the formation of mainly CSA in the presence of nitrogen and CSA and other unidentified products in the presence of oxygen.

Polymorphism and Pseudopolymorphism of the Antibacterial Nitrofurantoin

Abstract A physicochemical study of six crystalline modifications of the drug nitrofurantoin is presented. These forms comprise two polymorphs, two monohydrates, a DMF solvate and a DMSO solvate. The clathrate nature of the solvates as well as their thermal decompositions are described. The results of dissolution rate measurements for the polymorphs and monohydrates are discussed in relation to the formulation of the drug.

Identification of the Mebendazole Polymorphic Form Present in Raw Materials and Tablets Available in South Africa

A preformulation study of four different raw materials of mebendazole showed that three samples were polymorph C and the other polymorph A, or a mixture of form A and B. X-ray powder diffractometry and infrared spectroscopy indicated that this powder could be form B, but powder dissolution, for which a much slower dissolution was obtained, suggests polymorph A. Literature prescribes the use of polymorph C pharmaceutically, but generic manufacturers should be aware that forms other than C are still available on the market. The four mebendazole tablets currently available in South Africa were also tested and it was found that all of them contained polymorph C.

The effect of polymorphism on powder compaction and dissolution properties of chemically equivalent oxytetracycline hydrochloride powders.

In South Africa, oxytetracycline is identified as an essential drug; many generic products are on the market, and many more are being developed. In this study, six oxytetracycline hydrochloride powders were obtained randomly from manufacturers, and suppliers were compared. It was found that compliance to a pharmacopoeial monograph was insufficient to ensure the optimum dissolution performance of a simple tablet formulation. Comparative physicochemical raw material analysis showed no major differences with regard to differential scanning calorimetry (DSC), infrared (IR) spectroscopy, powder dissolution, and particle size. However, the samples could be divided into two distinct types with respect to X-ray powder diffraction (XRD) and thus polymorphism. The two polymorphic forms had different dissolution properties in water or 0.1 N hydrochloride acid. This difference became substantial when the dissolution from tablets was compared. The powders containing form A were less soluble than that containing form B.

Influence of surfactants and interactive mixing on the cohesiveproperties of a poorly wettable solid

Abstract The effect of different surface active agents and interactive mixing with high density carrier particles on the dispersion of cohesive furosemide particle agglomerates in aqueous mediums were studied. The individual mean volume particle size of the furosemide powder was 2.5 μm when measured with a dry dispersion apparatus. The particle size distribution was unimodal. Suspended in water the particle size distribution consisted of three distinguishable populations. The addition of surface active agents led to a decrease in the mean particle size, fewer populations were observed and the mean size of these populations were smaller. The addition of polyoxyethylene sorbitan monooleate, 0.011 g dm−3, leads to a decrease in the mean volume particle size from 32.31 μm measured in water, to 11.01 μm Depending on the mixing time, 64 min and longer, interactive mixing with high density sodium chloride particles was the most effective at dispersing the furosemide agglomerates but a bimodal particle size distribution was still observed. The mean volume particle size of furosemide particles mixed for 128 min, 7.79 μm was closest to the mean volume particle size measured with the dry dispersion technique.

Evaluation of Compatibility of Tablet Excipients with Albendazole and Closantel Using DSC and HPLC

The compatibility between albendazole and closantel, with commonly used tablet excipients, was assessed by studying drug-excipient mixtures mixed in 1:1 ratio and 1:1 ratios granulated with water and dried at 50°C for 1 hr with a differential scanning calorimeter (DSC) and high-performance liquid chromatograph (HPLC). Results showed that there were interactions between closantel and/or albendazole and some tablet excipients. For example, magnesium stearate reacted with both drugs and the interaction was observed by DSC and HPLC. Exposure of mixtures, and even the drugs, to heat and moisture resulted in deteriorated compatibility as seen by both DSC and HPLC, but especially HPLC. Overall poor correlation between DSC and HPLC results was observed.

The interconversion of the polymorphic forms of chloramphenicol palmitate (CAP) as a function of environmental temperature

AbstractWhen polymorph B of chloramphenicol palmitate (CAP) is heated at 82 °C for 1600 minutes it changes completely to the less soluble and less bioavailable polymorph A. When polymorph C, the most soluble polymorph, is grinded for a prolonged period it changes to polymorph A through B. We investigated the effect of the environmental temperature on the interconversion of polymorph C. This was done to determine the effect that heat generated during grinding could have on polymorph C.Samples of polymorph C was kept at 50 and 75 °C respectively. At predetermined intervals samples were withdrawn and differential scanning colorimetric (DSC) curves and Xray powder diffractograms recorded.Both samples changed to polymorph B but only the sample kept at 75 °C changed into A during the time the experiment was run. Therefore temperature control during storage and handling, especially grinding, of polymorph C and B is recommended to prevent conversion to the poorly soluble and less bioavailable polymorph A.

DIVERSE MODES OF SOLVENT INCLUSION IN CRYSTALLINE PSEUDOPOLYMORPHS OF THE ANTHELMINTIC DRUG NICLOSAMIDE

Single crystal X-ray structures of solvated forms of theanthelmintic drug Niclosamide reveal distinctly differentmodes of inclusion for different solvents. These modes are,respectively, cavity occupation by water molecules in 1 : 1niclosamide.H2O, channel occupation by tetrahydrofuranmolecules in 1 : 1 niclosamide.THF, and intercalation bytetraethylene glycol molecules in 2 : 1 niclosamide.TEG. Inall three compounds the host drug molecule adopts the same,nearly planar conformation, which is maintained by anintramolecular N′-H.O hydrogen bond. Host-guest recognitioninvariably involves hydrogen bonding between the drughydroxyl group and an oxygen acceptor atom of the solventmolecule. The observed modes of solvent inclusion can bereconciled with the behaviour of the crystals on heating.