Engineering of composite pharmaceuticals with improved physicochemical and mechanical properties
Authors
Hamisu, Mohammed HamisuAdvisors
Kaialy, WaseemIssue Date
2022-10
Metadata
Show full item recordAbstract
Tabletting by direct compression (DC) is the preferred method of tabletting as compared to granulation techniques because among other benefits it is simple, quick, and cost-effective. However, most pharmaceutical powders are not compressible via DC due to poor flowability, compactibility, compressibility, and the lack of proper elasticity. As such, formulation scientists use granulation techniques to obtain drug and/or excipient agglomerates with suitable compression properties. Due to challenges associated with the granulation techniques, co-processing using particle engineering techniques has recently become the preferred approach to improve powder physicochemical properties for DC to produce high-quality tablets that can serve the intended therapeutic purpose. Therefore, in this project, composite particles of three drugs (paracetamol, indomethacin, and metformin hydrochloride), which are notoriously known for their poor tabletting and dissolution properties were prepared and investigated to improve their tabletting and dissolution properties. The tabletting deficiency of paracetamol was overcome via composite particles prepared through cooling crystallisation and co-milling. The effect of the milling sequence to improve the flowability of the milled paracetamol composite particles was also investigated. The poor tabletability and dissolution of indomethacin were overcome via milling and freeze-drying. The poor tabletability of metformin HCl was overcome by co-freeze-drying in the presence of polyvinylpyrollidone (PVP). The solid-state properties of the engineered particles were characterised using SEM, laser diffraction, PXRD, FT-IR and TGA. The packing and flowability of the bulk powders were accessed via a density-based measuring technique and the tablets were characterised by friability, hardness (tensile strength), disintegration and dissolution properties. The results showed the composite particles to exhibit modified morphologies, hence remarkable tabletting, and dissolution improvements. Composite paracetamol particles prepared via cooling crystallisation were polyhedral in the absence of additive and irregular lumps in the presence of additives with mean diameters that range from 55.8 ± 0.2 μm to 155.2 ± 2.2 μm. The tablet tensile strength of commercial paracetamol could not be measured because the tablets capped immediately after ejection from the tablet die. Remarkably, composite particles showed ̴ 4-fold an increase in tensile strength as compared to the physical mixture. The composite particles engineered via milling were irregular and become smaller with increasing the milling time from 1 to 15 min (VMD ranged between 81.7 ± 0.6 and 20.4 ± 0.1 μm). Prolonging the milling time up to 20 min did not cause a decrease in particle size in comparison to 15 min (VMD = 22.9 ± 1.0 versus 20.4 ± 0.1 μm) which resulted in a decrease in tablet tensile strength. Generally, the tensile strength of paracetamol composite particles prepared via milling was ̴ 5-fold as compared to the physical mixture, which was better than that of cooling crystallisation. Composite paracetamol particles prepared using cooling crystallisation showed better flow properties (CI = 9.3 ± 0.3 to 15.7 ± 0.2%) than those prepared using milling (CI = 29.67 ± 0.6 to 42.7 ± 4.2%). Investigation of the milling sequence showed a significant improvement in the flowability of the milled composite particles (CI = 41.30 ± 3.1 vs 17.33 ± 0.6%). Although the sequentially milled composite particles generate a strong enough tablet to pass friability, the co-milled composite particles showed better tablet tensile strength than the sequentially milled composite particles (TS = 3.1 ± 0.03 vs 3.9 ± 0.05 MPa). The sequentially milled composite particles indicated a ~4-fold increase in tablet tensile strength in comparison to the physical mixture which was comparable to that of the tensile strength achieved by cooling crystallisation. Indomethacin composite particles prepared via milling showed enhancement in tablet tensile strength (~7-folds) in comparison to commercial indomethacin, and remarkable dissolution (DE (120min) = 91.23 ± 0.25 %, MDT = 9.86 ± 1.4 min and MDR = 1.97 ± 0.05 min-1) as compared to commercial indomethacin (DE (120 min) = 2.733 ± 0.09%, MDT = 57.81 ± 3.1 min, MDR= 0.047 ± 0.01 min-1). As compared to commercial indomethacin the composite indomethacin particles prepared via freeze-drying showed a ~5-fold increase in tensile strength and improved dissolution (DE (120min), 83.987 ± 3.83 versus DE (120 min), 2.733 ± 0.09%). Freeze-dried metformin composite particles were a mixture of irregular and elongated particles which showed improvement (~11-folds) in tablet tensile strength as compared to commercial metformin. In conclusion, highly crystalline composite particles of the drugs with improved physicochemical and mechanical properties were generated with unchanged polymorphic forms using particle engineering techniques (Cooling crystallisation, milling, and freeze-drying). The improved functional properties generated were attributed to the combined effect of change in particle morphology (size and shape), nature of the interaction between drug and excipients and the influence of processing conditions.Citation
Hamisu, M.H. (2022) Engineering of composite pharmaceuticals with improved physicochemical and mechanical properties. University of Wolverhampton. http://hdl.handle.net/2436/625290Publisher
University of WolverhamptonType
Thesis or dissertationLanguage
enDescription
A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.Sponsors
Petroleum Technology Development Fund (PTDF), Nigeria.Collections
The following licence applies to the copyright and re-use of this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International