Development and Analysis of Long Acting Parenteral Formulation

Abstract

newline A newly long acting parenteral formulation for pramipexole based on dissolution control type techniques was developed and in vitro as well as in vivo release studies were determined. Lauric, palmitic and pamoic acid were used as counter ions for the development of acid addition salt of pramipexole. The poorly water soluble salt was prepared using antisolvent addition method. Among all prepared salts, pramipexole pamoic acid salt have least water solubility and hence it was suitable for the formulation development. The 1:1 molar ratio of pramipexole and pamoic acid was optimized for salt formation. The HPLC method was developed and validated for the estimation of pramipexole in pramipexole pamoic acid salt for assay content, solubility and dissolution studies. newlineThe prepared salt aqueous solubility was retarded upto ~4500 folds as compared to pramipexole dihydrochloride monohydrate (native form) and ~100 fold as that of pramipexole free base. Pramipexole pamoic acid salt was characterized using various analytical techniques like Mass, DSC, NMR, GC, FTIR, PSD and XRPD. A low viscosity aqueous vehicle was prepared using sodium CMC, tween 80, propylene glycol, mannitol etc for the formulation of suspension which helps in the administration of developed salt. The reproducibility and repeatability of synthetic process was estimated by scale up studies and further accelerated stability studies were performed. newlineThe in vitro pramipexole release studies were determined in both powder as well as in suspension form by using modified USP apparatus 2 (Paddle with dialysis sac) and 4 (Flow through cell). Pramipexole pamoic acid salt showed discriminative dissolution profile based on its particle size distribution for both USP apparatus 2 and 4. The retarded drug releases profile in both the dissolution methods presented that the pramipexole pamoic acid salt possess prolonged release property as compared to commercially available pramipexole dihydrochloride monohydrate. newlineThe prepared salt suspension were checked for acute toxicity study and it was carried out in Swiss albino mice for 14 days. The LD50 was observed to be 250 mg/kg. In vivo studies were performed in rabbit showed that pramipexole pamoic salt suspension when administered intramuscularly was detected in rabbit plasma upto one week in compared to marketed formulation where drug was detected upto 4 hours only. LC-MS/MS method was developed and validated for the estimation of pramipexole in rabbit plasma. The developed depot formulation have controlled release and no burst effect was shown.