EFFECT OF FORMULATION VARIABLES ON GRANULATES OBTAINED BY MOISTURE ACTIVATED DRY GRANULATION

An increasing global concern regarding energy saving and a growing pharmaceutical interest towards the adoption of industrial continuous processing generate an appropriate scenario for the development of solid dosage forms by moisture activated dry granulation (MADG) processes, which eliminate granulate drying and sizing, and minimize granulation end point control by making it less sensitive to shear and processing time. The aim of this study was to contribute to further enlighten formulation aspects of an attractive granulation process such as MADG, using statistical techniques. A 2^(4-1) fractional factorial design was introduced to study the effect of formulation variables on granulates obtained and on their tablets. Multivariate techniques were applied in the evaluation of the products. Lactose monohydrate and mannitol, povidone K15 and copovidone, and microcrystalline cellulose, partially pregelatinized corn starch and amorphous silica were selected, as diluents, binders and moisture absorbents, respectively. Contact angle and drop penetration time of diluents and moisture absorbents were used to study their wettability. All of the granulates yielded tablets with appropriate aspect and tensile strength, low friability, short disintegration time and in most of the cases, good weight uniformity. The statistical techniques showed the influence of excipient selection in the granulation process. Lactose produced granulates which presented lower median size and more rounded granules, leading to tablets which showed greater weight uniformity than the other diluent mannitol. The binder PVP K15 increased granule mechanical strength, producing finished tablets with higher tensile strength and longer disintegration time than copovidone. The use of a second moisture absorbent improved granulate flowability and contributed to prevent granulate caking. Wettability studies provided useful information for guidance on preliminary excipient selection. In summary, MADG is an innovative and economical process which facilitates quality by design approach.