Category: Formulation and Quality
Purpose: Direct compression has gained popularity due to ease of manufacturing and fewer unit operations when compared to wet granulation. Nevertheless, Pharmaceutical Manufacturers continue to use wet granulation due to existing manufacturing set up, very low dose API (Eg: Hormonal API) etc. Excipients and related physical characteristics play a critical role in the performance of finished product quality especially in terms of Disintegration time (DT) & Dissolution of tablets. In this study various milled Lactose and direct compressible (DC) lactose were evaluated by utilising model Class I (Propranolol) & BCS class IV (Furosemide) at 10%W/W dose.
Methods: Wet granulation of BCS class I (Propranolol) & BCS class IV (Furosemide) were performed using various grades of milled lactose grades- Lactochem® fine powder, Pharmatose® 200M, Pharmatose® 350M. Particle Size distribution (PSD) of these grades are listed in Table 1. Wet granulation formulae contained 40% Pharmacel® MCC 101 whereas DC formulae contained Pharmacel® MCC 102. 1% Magnesium stearate was used as lubricant across all formulations. Direct compression of Propranolol & Furosemide were performed using SuperTab® 21AN, SuperTab® 11SD & SuperTab® 30GR (Refer Table 1 for PSD details ) separately. Disintegrant-Primojel® (Sodium starch glycolate) was evaluated at 2 & 4% for both Wet & Direct compression (DC) formulations. Therefore 12 formulations each were manufactured for Propranolol & Furosemide based formulations respectively. (6-wet granulation+6-DC). In total 24 formulations were manufactured and studied. Tabletting was carried out in the increasing order of Tablet tensile strength (TTS) and ranged from 0.5 to 2.2 Mpa for Propranolol formulations and from 0.5 to 3.3 Mpa for Furosemide formulations . Cadmach-CMB4-MT Tablet press and 8 mm round flat bevelled, D tooling was employed for 200mg Tablet weight. Disintegration test was performed as per USP < 701 > on 6 tablets. Dissolution was performed using current USP suggested method for Propranolol & Furosemide.
Results: Particle size distribution (PSD) of milled lactose (350M, LFP, 200M), DC lactose (21AN, 11SD, 30GR) [Table 1] in combination of concentration of Disintegrant (2 & 4%PJ) was found to influence DT & Dissolution of both Propranolol (Fig 1&2) & Furosemide ((Fig 3&4) wet & DC granulation formulations.
Pharmatose® 350M (350M)+4% Primojel (PJ) combination gave fastest DT both wet granulation & DC. SuperTab® 21AN based formulation in DC produced hardest tablets at 3.3 Mpa and therefore resulting DT were longer. But it must be noted that all formulations had DT< 15 minutes.
It should be noted that SuperTab® 30GR (30GR) based Propranolol & Furosemide formulation showed fastest DT. Interestingly for DC Furosemide formulation employing SuperTab® 21AN (21AN)+4% disintegrant (PJ) shows slower DT than with 2% disintegrant.
Dissolution of all formulation met requirements of USP i.e NLT 80% in 60min using pH 5.8 phosphate buffer 900ml Type II 50rpm for Furosemide formulations AND Not less than (NLT) 75% in 30min using USP with 1000 mL HCl , type 1 apparatus at 100 rpm for Propranolol formulations.
Conclusion: Selecting right excipient grade with certain PSD, optimal disintegrant concentration and right manufacturing method (DC vs Wet granulation) is necessary. In this study, DT results indicate that Lactose type with related PSD and disintegrant concentration should be optimised especially for BCS IV class of API (Eg: Furosemide) when using an highly compactible excipient type such as SuperTab® 21AN.