Abstract
Paracetamol (PCT) and propyphenazone (PRP) are analgesic drugs that are often combined in a single dosage form for enhanced pharmacological action. In this work, PCT and PRP were co-spray dried separately with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) using drug suspensions in polymer solutions as feed liquids. It was thought that because of polymer adherence to the surface of drug particles, the risk of PCT–PRP contact and interaction could be reduced. Such interaction may be caused by localized temperature gradients due to frictional forces during tableting, or during storage under harsh conditions. A worst-case scenario would be eutectic formation due to variations in powder mixture homogeneity since eutectic and therapeutic mass PCT/PRP ratios are close (65:35 and 60:40, respectively) and eutectic temperature is low (~56 °C). Uniform particle size, round shape, compaction improvement and faster release of the analgesics were important additional benefits of co-spray drying. Experimental design was first applied for each drug to optimize the polymer concentration on the yield of spray drying and melting point separation (Δmp) of heated binary mixtures of co-spray dried PCT/neat PRP, and vice versa, with the two drugs always included at their therapeutic 60:40 ratio. Optimal combinations with largest Δmp and production yield were: co-spray dried PCT (15% HPC) with neat PRP and co-spray dried PRP (10% HPMC) with neat PCT. Compression studies of these combinations showed tableting improvement due to the polymers, as reflected in greater work of compaction and solid fraction, greater fracture toughness and tablet strength, easier tablet detachment from the punch surface and ejectability. Faster release of both drugs was obtained from the tablet of co-spray dried PCT (15% HPC) with neat PRP. A one-month stability test (75% RH/40 °C) showed moisture-induced alteration tablet strength.
Highlights
Fixed-dose drug combinations in a single dosage form can provide more therapeutic or pharmacological value than each drug separately, as well as ensuring production cost savings
The results showed that the developed HPLC method is specific and, in all cases the peak purity index of both drugs was higher than 0.99999 (Supplementary Material, Figure S1)
This work explored theofbenefits of the application of co-spray drying for the production of a combination tablet two incompatible analgesic drugs: paracetamol (PCT)
Summary
Fixed-dose drug combinations in a single dosage form can provide more therapeutic or pharmacological value than each drug separately, as well as ensuring production cost savings. Paracetamol (PCT) is probably the antipyretic with the largest circulation and propyphenazone (PRP) is another analgesic that is commercially available as a combination product with PCT. A triple-combination tablet containing PCT, PRP and caffeine is commercially available under the trade name Saridon®. These combinatory treatments aim to enhance pharmacological action by drug synergy. PCT exhibits serious tableting problems due to the inherent poor compressibility and high elastic recovery which has been the subject of many studies [1,2,3]. Improvement of flow and compression of PRP was achieved by spherical crystallization [4]
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