M. M. De Villiers

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.

Structure-solubility relationship and thermal decomposition of furosemide.

Furosemide, a high ceiling diuretic, decomposes on heating and is very sparingly soluble in water. The aim of this study was to identify the thermal decomposition product(s) of furosemide and to calculate the activation energy needed for this reaction. This was done to gain a better understanding of the unusually low water solubility of this drug. The main thermal decomposition product was identified by nuclear magnetic resonance (NMR), mass spectrometry (MS), and infrared (IR) analysis as 4-chloro-5-sulfamoylanthranilic acid (saluamine), and the activation energy, calculated from thermogravimetric analysis (TGA) measurements, for this reaction was 47.7 (±1.93) kcal/mol. The experimentally measured activation energy was well below the normal 59 ± 4 kcal/mol needed for the cleavage of the C–N bond to form saluamine. This could possibly be explained by the weakening of the C–N bond through the I–effect of the furane ring and the delocalization of the electrons of the aniline nitrogen in the chlorosulfamoyl benzoic acid entity of furosemide. This decomposition of furosemide indicates the breaking of intramolecular bonds before those of intermolecular bonds (separation of individual furosemide molecules). Strong inter- and intramolecular bonds are a probable cause for the poor water solubility of furosemide because, when some of the inter- and intramolecular bonds that form part of the hydrogen bond network disappeared, as in the structurally related decomposition product saluamine, the aqueous solubility increased.

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.

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.

Comparing HPLC and UV Spectrophotometric Analysis Methods for Determining the Stability of Sorbic Acid in Nonionic Creams Containing Lactic Acid

This paper describes a comparison between ultraviolet (UV) spectrophotometric and high-performance liquid chromatographic (HPLC) methods of analysis for the determination of sorbic acid in nonionic creams containing lactic acid. Sorbic acid is an antimycotic agent and is used as a preservative in pharmaceuticals, cosmetics, and food products. UV spectrophotometric analysis was done by calculating the concentration of remaining sorbic acid from the absorbance values and the molar extinction coefficient E258M = 24,080. A decrease in absorbance at 258 nm was accompanied by a simultaneous increase in total carbonyls and monoaldehyde content and the appearance of a very weak absorption maximum between 215 and 225 nm. HPLC analysis was done with a Hypersil BDS C8 column with detection at 254 nm and employing a mobile phase consisting of a mixture of buffer and methanol (7:3 v/v) at a pH of 2.25. The buffer consisted of 0.85% H2SO4 in 17.5 mM KH2PO4. The validation results, together with statistical treatment of the data, demonstrated the reliability of both procedures. A drawback of the UV methods was, however, its lack of adequate measurement of sorbic acid stability at higher temperatures. For these assays, the HPLC method was found to be adequate, and it should therefore be used to obtain accurate stability data for sorbic acid in creams.

Dissolution from ordered mixtures: The effect of stirring rate and particle characteristics on the dissolution rate.

AbstractDifferent particle size fractions of three carriers were used to prepare ordered mixtures of frusemide. The dissolution of these mixtures were compared with a frusemide suspension and pure frusemide agglomerates by the USP XXI paddle method at three rotational speeds.The dissolution of mixtures containing a highly soluble carrier (sodium chloride) were comparable to the suspension depending on the particle size of the carrier. Insoluble carriers (dicalciumphosphatedihydrate and microcrystalline cellulose) increased the dissolution, but the enhancement depended on the rotational speed, the particle size and the density of the carrier.

Dissolution Rate A Measurement of the Deaggregation of Furosemide Agglomerates During An Interactive Mixing Process

AbstractAgglomerates of drug particles must be broken down and single particles attached to the carrier to ensure a completely random interactive mixture. Here it was found that the dissolution rates of samples from interactive mixtures compared to suspended furosemide was an indication of the deaggregation of furosemide agglomerates during an interactive mixing process. Deaggregation depended on the forces generated during mixing and was quicker when a high density carrier such as sodium chloride was used.