RESUME Effect of Physical State and Particle Size Distribution on Dissolution Enhancement of Nimodipine/PEG Solid Dispersions Prepared by Melt

Mixing and Solvent Evaporation

Solid dispersions are dosage forms whereby the drug is dispersed in a biologically inert matrix. They can be used to increase the dissolution rate of a drug with low aqueous solubility. Nimodipine is a drug substance of the 1,4dihydropyridine type that was developed by Bayer AG. Nimodipine has been licensed in Germany since 1984 for the prevention and treatment of ischemic neurological deficits caused by spasm of cerebral vessels following subarachnoid hemorrhage. Modification I (mod I) is a racemic compound and has a yellow color, whereas modification II (mod II) crystallizes as a conglomerate and it is almost white.

The preparation and storage condition of solid dispersions are crucial since changes may alter the dissolution characteristics of the active ingredients. There are many methods that has been used to monitor the stability of the amorphous state of the drug dispersed in polymer, they are wide angle x-ray diffractometry (WAXD), differential scanning calorimetry (DSC), differential thermoanalysis, solution calorimetry, infrared spectroscopy, and Fourier

Transform (FT)-Raman spectroscopy.

In this work, solid dispersions of nimodipine in higher molecular weight PEG 4000 are prepared. The objective is to study the effect of the preparation method of the physical structure. Thus, the 2 usual methods for solid dispersion preparation, which are the hot-melt and the solvent method, are used and 2 series of samples are prepared. Furthermore, the long term stability of nimodipine in these formulations is investigated. Physicochemical characterization of the

samples is performed by means of micro-Raman spectroscopy, WAXD, DSC, hot-stage microscopy (HSC), and scanning electron microscopy (SEM).

For materials and equipment, the micronized nimodipine with an assay of 101,2% was supplied from UQUIFA (Barcelona, Spain). It has a Tm = 125-128C, aqueous solubility of ~0.5 mg/L, and it is freely soluble in ethanol. The particle size was found to range from ~1 m (or less) up to 29 m. PEG 4000 was obtained from CLARIANT (Sulzbach, Germany). It has a molecular weight of 3898 g/mol, Tm = 54C, moisture content less than 0.5%, and viscosity at 20C and 50% relatively humidity 118 mPas. Sodium lauryl sulfate (SLS) was obtained from COGNIS (Fino Mornasco, Italy). All other materials and reagents were of analytical grade of purity.

For preparation of solid dispersions, 2 usual methods were used. They are hot-melt method and solvent evaporation. For the hot-melt method, physical mixtures of nimodipine and PEG were heated during stirring in a reaction tube immersed in an oil bath to 130C under an Argon atmosphere and held to this temperature. The prepared samples were stored at 25C in desiccator. And for the solvent evaporation, proper volumes of drug and polymer PEG were mixed in ethanol and the mixtures were ultrasonicated for 10 minutes. After the solvent has been evaporated for 2 days, the solid dispersions were stored at 25C in desiccator. The weight ratios of the 2 methods are the same. Samples were studied then by means of DSC, WAXD, SEM, micro-Raman spectroscopy, HSM, and dissolution testing.

WAXD can be used to studied about the behavior of the pure drug. Meltquenched nimodipine after 10 days of storage showed very limited crystallinity. However, after storage for 6 months at 25C and 60% RH, the sample appears to be quiet crystalline. The original sample showed reflections of nimodipine crystal mod I, in contrast to those after crystallization during long-term storage at room temperature after melt quenching, which showed reflection of the mod II. The DSC trace of the original, sample show a melting peak at 126, corresponding to mod I. Solution-crystallized nimodipine showed a lower melting temperature consistent with mod II. The polymorhism of nimodipine was also studied by

means of micro-Raman spectroscopy. Crystal mod I of nimodipine refers to the racemic compound while the mod II refers to the conglomerate. The 2 modifications can be distinguished by means of vibrational spectroscopy as they exhibit different spectra, which is Raman and infrared.

The dissolution behavior of solid dispersions can be altered during storage because of changes in the drugs physicochemical characteristics.the WAXD patterns of the solid dispersions prepared by the hot-melt method showed that in both cases (after storage for 10 days and also after 6 months) the patterns were almost identical, showing crystal reflections of both the drug and PEG. But the peaks of the crystalline nimodipine were weak. PEG crystallizes first and its crystals offer the solid surface for drug crystals to nucleate. The drug in the solid dispersions crystallized faster than the pure nimodipine after quenching to room temperature. Raman was used for assessing the spatial distribution and state of the drug in its solid dispersions with PEG. Micro-Raman mapping of the samples showed that the drug did not exist in ideal dispersion and that area of crystalline mod I and mod II coexisted in the dispersions. To estimate the particle size distribution of the drug in the solid dispersions, SEM microphotographs were taken.

To explore the effect of the preparation method, a second series of solid dispersions was prepared, it is called solvent evaporation method. In the WAXD patterns of these samples, the nimodipine crystal reflections appeared and they became stronger with increasing drug content. WAXD patterns of the samples after 6 months showed no increase in crystallinity or change in crystal modification of the drug. Micro-Raman mapping for the 10/90 and 50/50 wt/wt samples resulted images that were in complete contrast to those obtained from melt samples. The most notable difference is that the observed crystals are predominantly mod II. For the same overall drug content, in the samples from solvent evaporation, both the crystallinity of the drug and also the average crystal size are larger than in samples from melt. SEM microphotographs revealed existence of particles of ~5 m or less in general of these dispersions, but the size increased with increasing drug content. The HSM study revealed the

presence of the drug particles in the melt of PEG. Both DSC and HSM observations showed a progressive dissolution of the drug in the polymer melt.

Characterization of various nimodipine samples prepared by different methods showed that both crystal forms, i.e. racemic compound or conglomerate, may appear and the relative portions of the forms depend on the sample preparation condition. Nimodipine shows a low Tg value (20C) and crystallizes slowly during storage at room temperature. For higher drug content, recrystallization led to formation of mod I crystals in samples from melt, and to mod II crystals in samples from solvent evaporation. In the solid dispersions the drug was stabilized. Micro-Raman proved to be a powerful tool for characterization of solid dispersions. It revealed differences not only in the crystalline state, but also in the amorphous state of drug.