Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
Hydrophilic matrices are a principal technology used for extended release (ER) oral dosage forms and a recent review concluded that their development is currently one of the most important challenges in pharmaceutical research. High molecular weight polyethylene oxides (PEOs) have been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) for the manufacture of controlled release matrix tablets. It is known that PEO's are prone to oxidative degradation which can occur by chain scission and can be catalyzed by metal ions. In this study, we investigated the stability of PEO matrix tablets, of different molecular weight, containing diltiazem hydrochloride, when stored at 40 °C. The results show that there were dramatic increases in the release rate of the diltiazem following storage over only a few weeks, resulting in immediate release profiles after eight weeks, even for the highest molecular weight grade. We employed Gel permeation chromatography (GPC), viscosity and differential scanning calorimetry (DSC) techniques to try and determine the underlying causes of these dramatic shifts in dissolution profiles on storage. The results showed that there were significant decreases in the molecular weight of the PEO's during storage. The second part of the study looked at the addition of three different levels of vitamin E succinate to the tablets. The results clearly demonstrate the ability of the added antioxidant to reverse the significant reductions in molecular weight seen using GPC, viscosity and DSC. Importantly the addition of the antioxidant was able to stabilize the release profile of the diltiazem especially when present at a 1% level. Researchers and those working in pharmaceutical development should be aware of the potential stability risks when making matrix tablets containing PEO's and may wish to consider the addition of an antioxidant to the tablet formulation.
Psyllium has a mucilaginous property that makes it a good candidate to be utilized as an excipient in the preparation of controlled release systems. Various formulations were prepared using theophylline as a model drug and investigated with view to achieve an ideal slow drug release profile. The addition of HPMC to psyllium significantly reduced burst release however the percentage of drug release within a 12 h period was too slow and thereby inadequate. This was overcome by the addition of lactose as hydrophilic filler which enabled a slow release with roughly 80% drug release in 12 h. The inclusion of HPMC within psyllium formulations changed the drug release kinetics from Fickian diffusion to anomalous transport. Granulated formulations demonstrated slower drug release than ungranulated or physical mixture and caused a change in dissolution kinetics from Fickian diffusion to anomalous transport. Milled granules showed more efficient controlled drug release with no burst release. Milling of the granules also changed the drug release kinetics to anomalous transport. Although, psyllium was proved to be a promising polymer to control the drug release, a combination of psyllium-HPMC and formulation processes should be considered in an attempt to achieve a zero-order release.
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