Abstract
Paracetamol crystals often exhibit poor compressibility properties, which results in capping issues. The Particle Size Distribution (PSD) of paracetamol was engineered to improve the compressibility of paracetamol crystals. This was accomplished by growing paracetamol crystals in the presence of additives. The active pharmaceutical ingredient Phenacetin and impurity 4-chloroacetanalide were used to modify the crystal properties of paracetamol. In solution, the phenacetin or 4-chloroacetanalide molecules adsorb onto the paracetamol crystal faces selectively (110 or 011) and inhibit the further growth of the paracetamol crystal and consequently, the paracetamol crystal growth is reduced substantially. For controlling the PSD of crystal to improve the compressibility of paracetamol crystals, a set of cooling crystallization experiments in the presence of additive was designed. According to a statistical experimental design, the cooling rate was the most effective parameter. The PSD was reduced when paracetamol crystallized from the controlled crystallization in the presence of less than 3 mol% of both additives. These smaller particles increased almost four-fold the compressibility of paracetamol in comparison to the commercial material. Moreover, tablets were prepared for each formulation using a direct compaction method. The results illustrated that a higher tablet hardness of paracetamol was achieved by tailoring the paracetamol crystal size distribution. In addition, the tablet disintegration time was higher for the formulation with increased hardness. Overall, this work presents the potential use of structurally similar compounds as additives to alter the mechanical properties of an API.
Highlights
Crystallization is the major unit operation in manufacturing solid dosage oral formulations, as the properties of the finished product are highly dependent on the crystal attributes of Active Pharmaceutical Ingredient (API)
It can be seen that higher tensile strength levels have been obtained for formulations containing paracetamol with CA as an additive, which is due to its higher compressibility and smaller particle size distribution
The structurally similar additives were chosen because they can adsorb on the surface of paracetamol crystals to stop the growth and lead to the smaller paracetamol crystals
Summary
Crystallization is the major unit operation in manufacturing solid dosage oral formulations, as the properties of the finished product (e.g. tablets) are highly dependent on the crystal attributes of Active Pharmaceutical Ingredient (API). Current industrial standards rely on adding binders, lubricants and disintegrants such as polyvinylpyrrolidone (PVP), gelatine or starch derivatives to improve the tabletting properties (Di Martino et al, 1996; Di Martino et al, 1997; Fachaux et al, 1995) These techniques suffer from common limitations such as lower disintegration time (and lower drug release rate) of the solid-dosage forms (Andrews, 2007). In this study the form of paracetamol crystal (form I) is not changing after introducing the additives, the habit of crystals are changing and the better compression behaviour were observed This allows one to directly compress into (binder-free) high-dosage tablets of a fast-releasing drug.
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