Wilna Liebenberg

Preparation and physicochemical characterization of 5 niclosamide solvates and 1 hemisolvate

The purpose of the study was to characterize the physicochemical, structural, and spectral properties of the 1∶1 niclosamide and methanol, diethyl ether, dimethyl sulfoxide, N,N dimethylformamide, and tetrahydrofuran solvates and the 2∶1 niclosamide and tetraethylene glycol hemisolvate prepared by recrystallization from these organic solvents. Structural, spectral, and thermal analysis results confirmed the presence of the solvents and differences in the structural properties of these solvates. In addition, differences in the activation energy of desolvation, batch solution calorimetry, and the aqueous solubility at 25°C, 24 hours, showed the stability of the solvates to be in the order: anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > methanol solvate > dimethyl sulfoxide solvate > N,N dimethylformamide solvate. The intrinsic and powder dissolution rates of the solvates were in the order: anhydrate > diethyl ether solvate > tetraethylene glycol hemisolvate > N,N dimethylformamide solvate > methanol solvate > dimethyl sulfoxide solvate. Although these nonaqueous solvates had higher solubility and dissolution rates than the monohydrous forms, they were unstable in aqueous media and rapidly transformed to one of the monohydrous forms.

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.

Quality evaluation of generic drugs by dissolution test: changing the USP dissolution medium to distinguish between active and non-active mebendazole polymorphs

Mebendazole is practically insoluble in water and studies of its polymorphism has led to the identification and characterization of three polymorphic forms (A, B, C) displaying solubility and therapeutic differences that show that polymorph C is therapeutically favored. The objective of this study was to adjust the USP dissolution test for mebendazole so that it was able to distinguish between the dissolution properties of three mebendazole polymorphs. This would provide generic manufacturers with one more test to ensure that the therapeutically active polymorph C is used. The results obtained in this study show that the USP dissolution test conditions were not able to distinguish between the dissolution properties of completely dispersed mebendazole polymorphs with comparable particle sizes. When sodium lauryl sulfate was removed from the dissolution medium, the percentage dissolved versus time profiles changed so that polymorph C dissolved faster (70% within 120 min) compared to polymorph B (37% within 120 min) and polymorph A (20% within 120 min).

Effect of para-Sulfonato-Calix[n]arenes on the Solubility, Chemical Stability, and Bioavailability of a Water Insoluble Drug Nifedipine

This study reports the use of para-sulphonato calix[8]arene to produce stable complexes with improved bioavailability for nifedipine, a calcium-channel blocker that is practically insoluble in water. Thermal analysis and electrospray ionisation mass spectroscopy confirmed that nifedipine formed complexes with the calixarenes in a size dependent way. The most stable, soluble complexes was formed with para-sulphonato calix[8]arene. Complexation was weakest with the calix[4]arene while complexation with the calix[6]arene was intermediate. However, the calix[4 and 6]arenes changed the chemical stability of the drug in solution because significant amounts of the nitroso-pyridine derivative was produced, proposing an interaction between the nifedipine bearing a H substituent at the N-1 position and the calixarenes. This oxidative degradation of the drug was greatest when combined with the calix[6]arene. Simultaneous oral ingestion of the calix[6 or 8]arenes significantly increased the bioavailability of the drug after oral administration in male Sprague-Dawley rats while not influencing CYP3A activities in the liver. The pharmacokinetic parameters of the nifedipine: para-sulfonato calix[8]arene complexes showed it was bioequivalent to a nifedipine PEG-solution. The absolute bioavailability for both formulations was ca. 60 %.

Dissolution properties of piroxicam powders and capsules as a function of particle size and the agglomeration of powders.

The poor dissolution characteristics of relatively insoluble drugs have long been a problem to the pharmaceutical industry. An example is piroxicam, a highly potent anti-inflammatory agent. In many countries, a large number of generic piroxicam products are available to the prescriber. The aim of this study was to investigate the cause of the dissolution problems experienced by manufacturers of generic piroxicam capsules. Two raw material batches and the dissolution properties of several piroxicam capsules were studied. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) results showed that the two raw material samples were identical with respect to polymorphic modification. The particles of powder 1 were smaller than those of powder 2, but the dissolution of powder 1 was much slower than that of powder 2. The dissolution results for the capsules showed a marked difference among different brands, with capsule C not meeting the USP tolerance. Adding surfactant to the dissolution medium increased the dissolution of both powder 1 and capsule C. Failure of powder 1 or capsule C to meet USP dissolution criteria could result in differences in product efficacy, as well as in potential side effects. Such observations should be taken into account along with other relevant considerations when decisions regarding the generic substitution of oral piroxicam products are made.

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.

The Dissolution and Complexing Properties of Ibuprofen and Ketoprofen when Mixed with N-Methylglucamine

The objectives of this study were to improve the aqueous dissolution properties of the poorly soluble nonsteroidal anti-inflammatory drugs ibuprofen and ketoprofen and to explore the use of N-methylglucamine (meglumine) to enhance the dissolution properties of poorly water-soluble drug powders. Changes in both differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) results indicate that possibly complexes were produced between ibuprofen and N-methylglucamine. Similar changes were not observed for equivalent ketoprofen and N-methylglucamine mixtures. The results of solubility and dissolution studies in water at 25 degrees C and 37 degrees C showed that N-methylglucamine, in mixtures and coprecipitates, increased the solubility, intrinsic dissolution, and powder dissolution of ketoprofen and ibuprofen. N-Methylglucamine significantly improved the solubility and dissolution properties of both ibuprofen and ketoprofen even when DSC and XRD behavior did not indicate the formation of complexes.

Recrystallization of Active Pharmaceutical Ingredients

Recrystallization can be described simply as a process whereby a crystalline form of a compound may be obtained from other solid-state forms, being themselves crystalline or amorphous, of the same substance. Recrystallization is the process most often employed for the intermediate separation and last-step purification of solid active pharmaceutical ingredients (APIs) (Shekunov & York, 2000; Tiwary, 2006). Chemical purity is however not the only property of a pharmaceutical active that will affect its performance. Crystal structure (Table 1), crystal habit (Table 2) and particle size all play a part. Polymorphism (different crystal structures of the same substance) affects the physico-chemical properties and stability of an API, whereas crystal habit and particle size mostly affect various indices impacting on dosage form production and performance: particle orientation; flowability; packing and density; surface area; aggregation; compaction; suspension stability; and dissolution (Blagden et al., 2007; Doherty & York, 1988; Tiwary, 2006).

Crystallization of toxic glycol solvates of rifampin from glycerin and propylene glycol contaminated with ethylene glycol or diethylene glycol.

This study was initiated when it was suspected that syringe blockage experienced upon administration of a compounded rifampin suspension was caused by the recrystallization of toxic glycol solvates of the drug. Single crystal X-ray structure analysis, powder X-ray diffraction, thermal analysis and gas chromatography were used to identify the ethylene glycol in the solvate crystals recovered from the suspension. Controlled crystallization and solubility studies were used to determine the ease with which toxic glycol solvates crystallized from glycerin and propylene glycol contaminated with either ethylene or diethylene glycol. The single crystal structures of two distinct ethylene glycol solvates of rifampin were solved while thermal analysis, GC analysis and solubility studies confirmed that diethylene glycol solvates of the drug also crystallized. Controlled crystallization studies showed that crystallization of the rifampin solvates from glycerin and propylene glycol depended on the level of contamination and changes in the solubility of the drug in the contaminated solvents. Although the exact source of the ethylene glycol found in the compounded rifampin suspension is not known, the results of this study show how important it is to ensure that the drug and excipients comply with pharmacopeial or FDA standards.