The influence of fillers on theophylline release from clay matrices

Abstract: The objectives of this study were to investigate the suitability of magnesium aluminium silicate (MAS) (Veegum®) to control drug release of a model drug, theophylline, from tablet matrices. To this end, the performance of three commonly used fillers namely: lactose, microcrystalline cellulose (Avicel PH102; MCC), and pre-gelatinized starch, Starch 1500 PGS), were evaluated against Veegum®. The physico-mechanical properties of the tablet matrices were studied along with dissolution studies to determine the effect of single or binary mixtures of the excipients on the drug release pattern. A DSC hydration methodology was also employed to characterize the states of water present in the tablet matrices and to determine any impact on drug release. Formulations containing MAS alone produced compacts with the lowest hardness (4.5 kp) whereas formulations containing MCC alone produced the hardest tablets (17.2 kp). Dissolution studies suggested that matrices containing MAS alone released the theophylline quickest as compared to lactose, MCC or PGS. It was difficult to establish a trend of the bound and free water states in the tablet matrices; however the formulation containing only MAS had the highest bound water at 29 %. The results therefore show that theophylline does not interact with MAS. As such the dominant factor in controlling drug release using MAS requires interaction or intercalation with a cationic drug. In the absence of this however, other excipients can play a role in controlling drug release. Keywords: Veegum, clay matrices, DSC hydration, Magnesium aluminium silicate, filler

Evaluation of sesamum gum as an excipient in matrix tablets

In developing countries modern medicines are often beyond the affordability of the majority of the population. This is due to the reliance on expensive imported raw materials despite the abundance of natural resources which could provide an equivalent or even an improved function. The aim of this study was to investigate the potential of sesamum gum (SG) extracted from the leaves of Sesamum radiatum (readily cultivated in sub-Saharan Africa) as a matrix former. Directly compressed matrix tablets were prepared from the extract and compared with similar matrices of HPMC (K4M) using theophylline as a model water soluble drug. The compaction, swelling, erosion and drug release from the matrices were studied in deionized water, 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using USP apparatus II. The data from the swelling, erosion and drug release studies were also fitted into the respective mathematical models. Results showed that the matrices underwent a combination of swelling and erosion, with the swelling action being controlled by the rate of hydration in the medium. SG also controlled the release of theophylline similar to the HPMC and therefore may have use as an alternative excipient in regions where Sesamum radiatum can be easily cultivated

Starch-free grewia gum matrices: Compaction, swelling, erosion and drug release behaviour

Polysaccharides are suitable for application as hydrophilic matrices because of their ability to hydrate and swell upon contact with fluids, forming a gel layer which controls drug release. When extracted from plants, polysaccharides often contain significant quantities of starch that impacts upon their functional properties. This study aimed to evaluate differences in swelling, erosion and drug release from matrix tablets prepared from grewia gum (GG) and starch-free grewia gum (GDS) extracted from the stems of Grewia mollis. HPMC was used as a control polymer with theophylline as a model drug. Swelling, erosion, and in-vitro release were performed in deionized water, pH1.2 and pH6.8 media. The Vergnaud and Krosmeyer-Peppas model were used for swelling and drug release kinetics, respectively. However, linear regression technique was used to determine the erosion rate. GDS compacts were significantly harder than the native GG and HPMC compacts. GDS matrices exhibited the fastest erosion and drug release in deionised water and phosphate buffer compared with the GG and HPMC. At pH1.2, GDS exhibited greater swelling than erosion, and drug release was similar to GG and HPMC. This highlights the potential of GDS as a matrix for controlled release similar to HPMC and GG at pH1.2 but with a more rapid release at pH6.8. GDS may have wider application in reinforcing compacts with relatively low mechanical strengt

Physiochemical and drug release properties of liquisolid formulations in comparison to their physical mixture counterparts

A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy (PhD).Various techniques have been used for modifying the release properties of drugs over the past years. Techniques such as liquisolid technology have raised a lot of interest in many researchers which can be employed to enhance or sustain dissolution. Various liquisolid (LS) tablets of diltiazem containing Polysorbate 80 as a non-volatile solvent for sustained release were prepared. PolyoxTM is an attractive pharmaceutical polymer used in controlled release dosage forms mainly because of its insensitivity to the pH of the biological medium and ease of production. The aim of this study was to investigate the influence of several formulation factors i.e., the PolyoxTM grade at different molecular weight (MW), PolyoxTM particle size and ratio, the AEROSIL® grade, the use of diluent, polymer type and the drug type as well as their interactions on drug release from LS formulation in comparison to their physical mixture (PM). The result showed that PolyoxTM MW was a key determining step in achieving sustained release, with the higher MW of PolyoxTM resulting in a more delayed release profile. The delayed DTZ release could be related to the rate and extend of hydrogel formation on the tablet surface. The P–CMRs and net–CMRs of both LS and PM formulation powders also showed increasing trends with increasing the MW of PolyoxTM. The release of DTZ from both LS and conventional tablets showed mostly decreasing trends with increasing PolyoxTM concentration and decreasing PolyoxTM particle size distribution. This could be attributed to the formation of stronger and thicker gel layers on the tablet surfaces in the case of higher concentrations of PolyoxTM. The results also showed LS tablets to produce slower release of drug than their PM counterparts, regardless of PolyoxTM particle size. The release profile of the DTZ from both LS tablets and their counterpart PM tablets showed decreasing trends with increasing the surface area of hydrophilic AEROSIL® (from 65 m2/g to 225 m2/g). This could be due to the higher tensile strength (TS) of the tablets containing AEROSIL® particles with higher surface area compared to those prepared using AEROSIL® particles having lower surface areas. Also, the result showed that comparing the different diluents showed that hydrogenated vegetable oil (HVO) provided the slowest release pattern of DTZ across diluents used in both the LS compacts and PM tablets. This could be attributed to hydrophobicity imparted by HVO to matrix system when in contact with aqueous medium it takes a longer time to penetrate into the tablet. Drug release from LS tablets was affected by the polymer type. The release was in the order: Eudragit® RL < Eudragit® RS < Hypromellose < PolyoxTM < Psyllium. Hydrophilic Psyllium provided a slowest DTZ release across the different polymers used in the preparation of both the LS and PM compacts. The incorporation of Psyllium into PolyoxTM further elicited a decrease in drug release rate from individual polymer matrices. This was ascribed to the reduced entrance of aqueous media into the matrix due to the presence of the stronger viscose gel within the two hydrophilic matrices compared to individual Psyllium and PolyoxTM. The ratio between PolyoxTM and Psyllium has critically influenced diltiazem release profile. The results showed that matrices containing (Psyllium:PolyoxTM) at 1:1 ratio can slow down the drug release more than the matrices compacts containing 1:3 and 3:1 (Psyllium:PolyoxTM) ratio. The results also suggest that the ii combination of PolyoxTM and Psyllium at 1:1 ratio showed robust dissolution against pH and rotational speed and therefore indicates an appropriate sustained-release profile. The dissolution rate of PolyoxTM:Psyllium from different pure drugs showed a decreasing trend with an increase in their solubility. The solid state analysis studied in this work confirms the presence of a fraction of the drug mass in a solubilised state within polysorbate 80 in LS powders. Regardless of all variables used in this study, LS formulations showed slower drug release than their PM counterparts. In conclusion, the mechanical properties of LS formulation are poor in comparison to their counterpart PM. Therefore, further work is required to improve the hardness of LS tablet comprehensively.Tertiary Education Trust Fund (TETFUND

Crystal engineering of ibuprofen using starch derivatives in crystallization medium to produce promising ibuprofen with improved pharmaceutical performance

Ibuprofen exhibits poor flow, poor compaction and dissolution behaviour, and it is prone to capping after ejection from the die. Therefore, the aim of the present research was to engineer ibuprofen crystals in the presence of two disintegrants (starch and sodium starch glycolate) in order to improve its flow, compactibility and dissolution behaviour simultaneously. To this end ibuprofen and different concentrations of disintegrant (0.25 to 10% w/w in case of starch and 0.25 to 7% w/w in case of sodium starch glycolate) were dissolved in ethanol and water respectively. The ibuprofen solution was then added to the aqueous solutions containing the different concentrations of disintegrant. Ibuprofen precipitated within 10 min and the crystals were separated and dried for further studies. The obtained crystals were characterized in terms of flow, density, tablet hardness, dissolution behaviour and solid state. The results showed most of engineered ibuprofen to have better flow with a high compactibility. The results also showed that an increase in the concentration of starch in the crystallization medium resulted in a reduction in the hardness of ibuprofen tablets, but this was not the case for ibuprofen samples engineered in the presence of sodium starch glycolate. It is interesting to note that although engineered ibuprofen showed superior dissolution as compared to untreated ibuprofen, the highest concentration of starch (10%) or sodium starch glycolate (7%) slowed down the release remarkably due to an increase in the viscosity of the dissolution medium around drug particles. Solid state analysis (FT-IR, XRPD and DSC) ruled out the presence of different polymorphic forms and also any interaction between these disintegrants and ibuprofen. In conclusion, the engineering of ibuprofen in the presence of disintegrant showed how properties such as flow, compaction and dissolution behaviour can be simultaneously manipulated to suit a desired application

Engineering of composite pharmaceuticals with improved physicochemical and mechanical properties

A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.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.Petroleum Technology Development Fund (PTDF), Nigeria

Evaluation of the drug solubility and rush ageing on drug release performance of various model drugs from the modified release polyethylene oxide matrix tablets

Hydrophilic matrix systems are currently some of the most widely used drug delivery systems for controlled-release oral dosage forms. Amongst a variety of polymers, polyethylene oxide (PEO) is considered an important material used in pharmaceutical formulations. As PEO is sensitive to thermal oxidation, it is susceptible to free radical oxidative attack. The aim of this study was to investigate the stability of PEO based formulations containing different model drugs with different water solubility, namely propranolol HCl, theophylline and zonisamide. Both polyox matrices 750 and 303 grade were used as model carriers for the manufacture of tablets stored at 40 °C. The results of the present study suggest that the drug release from the matrix was affected by the length of storage conditions, solubility of drugs and the molecular weight of the polymers. Generally, increased drug release rates were prevalent in soluble drug formulations (propranolol) when stored at the elevated temperature (40 °C). In contrast, it was not observed with semi soluble (theophylline) and poorly soluble (zonisamide) drugs especially when formulated with PEO 303 polymer. This indicates that the main parameters controlling the drug release from fresh polyox matrices are the solubility of the drug in the dissolution medium and the molecular weight of the polymer. DSC traces indicated that that there was a big difference in the enthalpy and melting points of fresh and aged PEO samples containing propranolol, whereas the melting point of the aged polyox samples containing theophylline and zonisamide was unaffected

Hydroxypropyl Methyl Cellulose-Encapsulated Niosomes for Enhanced Oral Delivery of Curcumin as Antihypercholesterolemia: Optimization, In Vitro, and In Vivo Study

Hypercholesterolemia prompts the exploration of curcumin as a potential treatment. Due to its low solubility and bioavailability, oral use in drug delivery systems is still limited. This research aims to address these limitations by increasing the efficiency of curcumin via encapsulation system in niosomes combined with Hydroxypropyl Methyl Cellulose (HPMC). The optimal niosome curcumin (NioC) formulation was determined through Response Surface Methodology (RSM) with %EE and %DR as the responses, and the amount of curcumin, span 60, and cholesterol as the independent variables. In vivo experiments in mice were carried out to study the delivery performance of HPMC-NioC against hypercholesterolemia. The results of RSM optimization in NioC formulation showed that the optimum formula was 2.5 mg curcumin, 16 mg cholesterol, and 11 mg Span 60. NioC encapsulation resulted in a high %EE of 99.89%. In vitro test showed a %DR of 30.11% over a 20-hour. In vivo testing showed a significant reduction in total cholesterol levels, i.e. 26.23% during 20 days of treatment