Browsing by Subject "preformulointi"

Poorly water-soluble drugs are challenging to formulate as solid oral dosage forms because of their inadequate solubility in the gastro-intestinal tract. Amorphous solid dispersions (ASDs) are a proven method of increasing the oral bioavailability of poorly water-soluble drugs through drug supersaturation. Downstream processing of ASDs into oral tablets has gained academic interest in recent years. However, minitablets, which are tablets smaller than 4 mm in size, have not received the same level of attention. Minitablets have been cited as a promising dosage form for children, the elderly and in veterinary use because of their good compliance, flexible dosing, and ease of swallowing. In this work, 15 different blends of microcrystalline cellulose and lactose have been characterized for their suitability in the formulation of an ASD of spray-dried poorly soluble indomethacin in PVP K 29-32 or HPMCAS MF as minitablets. Minitablets were compressed at the compression forces ~1000 N and ~1500 N. The flowability of the blends were evaluated based on the Carr’s indices, Hausner ratios and angles of repose. From the most promising blends, 3.0 mm placebo minitablets were manufactured. A mixing test using colored beetroot powder was used to determine the optimal mixing time. The finished tablets were tested for their uniformity of mass, crushing strength, height, and disintegration. Based on their Carr’s indices and Hausner ratios, Vivapur 105, Vivapur 200, Pharmatose 200M and Pharmatose 80M had the best flowabilities. Placebo minitablets were successfully manufactured from blends of these excipients except for the 1:1 ratio of Vivapur 105/Pharmatose 80M. The mixing test indicated that the optimal mixing time is 20 to 25 minutes. The mass variation for all placebo batches except the 1:3 ratio of Vivapur 105/Pharmatose 80M was less than 10 percent from the average mass and most batches therefore fulfilled the uniformity of mass requirement of the European Pharmacopoeia. For five of the batches, the variation was within 2.80 percent. The average crushing strengths were between 32.4 N and 79.7 N and increased with increasing compression force. All batches of placebo minitablets disintegrated within 6 to 19 seconds on average except the 1:3 ratio of Vivapur 105/Pharmatose 80M which took 90 seconds to disintegrate. Minitablets filled in capsules disintegrated within 124 to 167 seconds on average except for the previously mentioned slower disintegrating batch which disintegrated in 477 seconds. All placebo minitablets, individual or loaded into capsules disintegrated within 15 minutes thereby fulfilling the requirement of the European Pharmacopeia. When considering the results obtained for placebo minitablets, the 3:1 ratio blend of Vivapur 200/Pharmatose 200M with 0.5 % (w/w) magnesium stearate was found to be the most promising candidate for ASD formulation. This formulation was subsequently used as the basis for the manufacture of 3.0 mm minitablets containing 6.22 % (w/w) of a spray-dried dispersion of indomethacin and PVP K 29-32. Except for one outlier, the mass variation of these minitablets fell within 2.37 % of the average mass, thereby fulfilling the requirement of the European Pharmacopoeia. Single indomethacin-PVP minitablets disintegrated within 6 minutes and 38 seconds, and capsules containing twelve minitablets disintegrated within 10 minutes and 37 seconds, which also is accordance with the pharmacopoeia. At 80.3 to 80.4 N the crushing strength was at the upper end of the targeted range, but still adequate. Thus, the formulation developed in this study appears promising for the manufacture of minitablets containing 6.22 % of an amorphous indomethacin-PVP dispersion. This study demonstrated that minitablets could be manufactured from a spray-dried solid dispersion despite its poor flowability.

The pet medication industry is growing but there are still challenges especially in feline medication. Palatable flavours, efficient taste masking technologies and easily administrable dosage forms are needed to facilitate feline medication. Based on the literature review, there is only little information about cat's preference to individual flavours. The methods for palatability testing should be improved to achieve reliable results. Most common taste masking technologies are flavouring and tablet coating. In experimental section different flavours for taste masking were studied. Five main flavours were selected: phenylalanine, leucine and methionine as possibly good flavours and arginine and denatonium benzoate as bad flavours. In preformulation experiments tableting characteristics, thermal behaviour and crystal structure of flavours were analysed. The aim was also to study their possible incompatibilities with tablet excipients. The main compatilibility study method was X-ray powder diffraction (XRPD), but differential scanning calorimetry (DSC) was also used. Excipient povidone (PVP) was incompatible with nearly all of the main flavours. The use of lactose as an excipient was excluded because of the risk of the Maillard reaction. In tableting studies a tablet mass containing microcrystalline cellulose (MCC), calcium hydrogen phosphate dihydrate, mannitol, hydroxypropyl cellulose (HPC), crospovidone, talc and sodium stearyl fumarate was produced. Minitablets of diameter 3 mm without any flavours were compressed. Also minitablets with flavours phenylalanine and denatonium benzoate were compressed. Minitablets complied with the European Pharmacopoeia tests for uniformity of mass, disintegration and friability. However, characterization and handling of minitablets was found to be challenging due to very small size of the tablets. Minitablets are a promising technology for facilitating feline medication in the future.