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1.
Int J Pharm ; 575: 118908, 2020 Feb 15.
Article in English | MEDLINE | ID: mdl-31809859

ABSTRACT

A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. The results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the dissolution environment and PEO molecular weight.


Subject(s)
Amidines/chemistry , Azetidines/chemistry , Polyethylene Glycols/chemistry , Delayed-Action Preparations/chemistry , Drug Compounding , Drug Liberation , Tablets
2.
Int J Pharm ; 528(1-2): 705-713, 2017 Aug 07.
Article in English | MEDLINE | ID: mdl-28636894

ABSTRACT

The purpose of this study was to investigate the hydration behavior of two matrix formulations containing the cellulose derivative hydroxypropyl methylcellulose (HPMC). The two HPMC batches investigated had different substitution pattern along the backbone; the first one is referred to as heterogeneous and the second as homogenous. The release of both the drug molecule theophylline and the polymer was determined. Additionally, the water concentrations at different positions in the swollen gel layers were determined by Magnetic Resonance Imaging. The experimental data was compared to predicted values obtained by the extension of a mechanistic Fickian based model. The hydration of tablets containing the more homogenous HPMC batch showed a gradual water concentration gradient in the gel layer and could be well predicted. The hydration process for the more heterogeneous batch showed a very abrupt step change in the water concentration in the gel layer and could not be well predicted. Based on the comparison between the experimental and predicted data this study suggests, for the first time, that formulations with HPMC of different heterogeneities form gels in different ways. The homogeneous HPMC batch exhibits a water sorption behavior ascribable to a Ficks law for the diffusion process whereas the more heterogeneous HPMC batches does not. This conclusion is important in the future development of simulation models and in the understanding of drug release mechanism from hydrophilic matrices.


Subject(s)
Drug Liberation , Hypromellose Derivatives/chemistry , Methylcellulose/chemistry , Chemistry, Pharmaceutical , Delayed-Action Preparations , Polymers , Solubility , Tablets , Water
3.
J Control Release ; 187: 50-8, 2014 Aug 10.
Article in English | MEDLINE | ID: mdl-24818771

ABSTRACT

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion-time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed.


Subject(s)
Food-Drug Interactions , Hypromellose Derivatives/chemistry , Hypromellose Derivatives/pharmacokinetics , Adult , Diet, High-Fat , Fasting/metabolism , Ferric Compounds/chemistry , Gastric Mucosa/metabolism , Gastrointestinal Transit , Humans , Intestine, Large/metabolism , Intestine, Small/metabolism , Magnetic Phenomena , Male , Molecular Weight , Postprandial Period , Solubility , Tablets
4.
Eur J Pharm Biopharm ; 78(3): 470-9, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21316446

ABSTRACT

The release of theophylline and carbamazepine from matrix tablets composed of microcrystalline cellulose, lactose and hydroxypropyl methylcellulose (HPMC) was studied. The aim was to investigate the effect of different substituent heterogeneities of HPMC on the drug release from matrix tablets composed of either 35% or 45% HPMC. The release of the poorly soluble carbamazepine was considerably affected by the HPMC heterogeneity, and the time difference at 80% drug release was more than 12h between the formulations of different HPMC batches. This was explained by slower polymer erosion of the heterogeneous HPMC and the fact that carbamazepine was mainly released by erosion. In addition, results from magnetic resonance imaging showed that the rate of water transport into the tablets was similar. This explained the comparable results of the release of the sparingly soluble theophylline from the two formulations even though the polymer erosion and the swelling of the tablets were considerably different. Thus, it can be concluded that the drug release was highly affected by the substituent heterogeneity, especially in the case of carbamazepine, which was released mainly by erosion.


Subject(s)
Carbamazepine/chemistry , Drug Delivery Systems , Methylcellulose/analogs & derivatives , Theophylline/chemistry , Carbamazepine/analysis , Drug Carriers/chemistry , Drug Compounding , Excipients/analysis , Excipients/chemistry , Hypromellose Derivatives , Methylcellulose/analysis , Methylcellulose/chemistry , Particle Size , Pharmacokinetics , Polymers/chemistry , Porosity , Powders , Solubility , Tablets/chemistry , Theophylline/analysis
5.
Eur J Pharm Biopharm ; 77(1): 99-110, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21081160

ABSTRACT

This study investigates the effect of the chemical heterogeneity of hydroxypropyl methylcellulose (HPMC) on the release of model drug substances from hydrophilic matrix tablets. The hypothesis was that the release of drug substances could be influenced by possible interactions with HPMC batches having different chemical heterogeneity. The cloud point of the most heterogeneous batch was more affected by the model drug substances, methylparaben and butylparaben, and most by butylparaben with the lowest solubility. The different clouding behaviour was explained by the heterogeneously substituted batches being more associative and the more lipophilic butylparaben being able to interact more efficiently with the hydrophobic HPMC transient crosslinks that formed. Interestingly, tablet compositions of the heterogeneously substituted HPMC batches released the more soluble methylparaben at lower rates than butylparaben. The explanation is that the hydrophobic HPMC interactions with butylparaben made the gel of the tablet less hydrated and more fragile and therefore more affected by erosional stresses. In contrast, drug release from compositions consisting of the more homogeneously substituted batches was affected to a minor extent by the drugs and was very robust within the experimental variations. The present study thus reveals that there can be variability in drug release depending on the lipophilicity of the drug and the substituent heterogeneity of the HPMC used.


Subject(s)
Excipients/chemistry , Methylcellulose/analogs & derivatives , Pharmaceutical Preparations/chemistry , Chemical Phenomena , Delayed-Action Preparations/chemistry , Drug Compounding , Excipients/analysis , Gels , Hydrophobic and Hydrophilic Interactions , Hypromellose Derivatives , Kinetics , Methylcellulose/analysis , Methylcellulose/chemistry , Parabens/analysis , Parabens/chemistry , Reproducibility of Results , Solubility , Tablets , Transition Temperature , Viscosity
6.
Int J Pharm ; 401(1-2): 60-7, 2010 Nov 30.
Article in English | MEDLINE | ID: mdl-20883761

ABSTRACT

The release of a model drug substance, methylparaben, was studied in matrix tablets composed of hydroxypropyl methylcellulose (HPMC) batches of the USP 2208 grade that had different chemical compositions. It was found that chemically heterogeneous HPMC batches with longer sections of low substituted regions and lower hydroxypropoxy content facilitated the formation of reversible gel structures at a temperature as low as 37°C. Most importantly, these structures were shown to affect the release of the drug from matrix tablets, where the drug release decreased with increased heterogeneity and a difference in T80 values of 7h was observed between the compositions. This could be explained by the much lower erosion rate of the heterogeneous HPMC batches, which decreased the drug release rate and also released the drug with a more diffusion based release mechanism compared to the less heterogeneous batches. It can therefore be concluded that the drug release from matrix tablets is very sensitive to variations in the chemical heterogeneity of HPMC.


Subject(s)
Drug Carriers/chemistry , Methylcellulose/analogs & derivatives , Parabens/chemistry , Chemistry, Pharmaceutical , Hypromellose Derivatives , Methylcellulose/chemistry , Molecular Weight , Solubility , Tablets , Temperature , Viscosity
7.
Int J Pharm ; 389(1-2): 147-56, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20100556

ABSTRACT

The purpose of this study was to gain further understanding of how the substituent heterogeneity of hydroxypropyl methylcellulose, HPMC, affects the polymer release from hydrophilic matrix tablets. The hypothesis was that the heterogeneous substituent pattern facilitated hydrophobic interactions that increased the viscosity and therefore affected the release rate to a major extent. Polymer tablets were prepared from three heterogeneously substituted HPMC batches of the same substituent (2208) and viscosity (100 cps) grade. To elucidate the hypothesis, fractions of both the dissolved polymer and the tablet residue were collected from the dissolution bath and further characterised. The extensive characterisation showed that, although the dissolved bath fraction and the tablet residue had a similar average degree of substitution, the residue was more heterogeneously substituted. It was further revealed that the heterogeneous substituent pattern of the tablet residue facilitated the formation of soluble gel-like components already at room temperature, which increased the viscosity. The viscosity increased by 150% at temperatures correlated to the dissolution bath, and it was thus concluded that the gel-like components grew in size with temperature. Finally, much lower release rates were obtained by tablets composed of the residue compared to tablets composed of the bath fraction, which clarified the hypothesis.


Subject(s)
Drug Carriers/chemistry , Methylcellulose/analogs & derivatives , Polymers/chemistry , Chemistry, Pharmaceutical/methods , Hypromellose Derivatives , Methylcellulose/chemistry , Solubility , Tablets , Temperature , Viscosity
8.
Biomacromolecules ; 10(3): 522-9, 2009 Mar 09.
Article in English | MEDLINE | ID: mdl-19173653

ABSTRACT

Industrially produced hydroxypropyl methylcellulose (HPMC) is a chemically heterogeneous material, and it is thus difficult to predict parameters related to function on the basis of the polymer's average chemical values. In this study, the solution behavior of seven HPMC batches was correlated to the molecular weight, degree of substitution, and substituent pattern. The initial onset of phase separation, so-called clouding, generally followed an increased average molecular weight and degree of substitution. However, the slope of the clouding curve was affected by the substitution pattern, where the heterogeneously substituted batches had very shallow slopes. Further investigations showed that the appearance of a shallow slope of the clouding curve was a result of the formation of reversible polymer structures, formed as a result of the heterogeneous substituent pattern. These structures grew in size with temperature and concentration and resulted in an increase in the viscosity of the solutions at higher temperatures.


Subject(s)
Methylcellulose/analogs & derivatives , Hypromellose Derivatives , Methylcellulose/chemistry , Molecular Weight , Particle Size , Solutions , Surface Properties , Temperature , Viscosity
9.
Eur J Pharm Sci ; 36(4-5): 392-400, 2009 Mar 02.
Article in English | MEDLINE | ID: mdl-19049865

ABSTRACT

Polymer release from hydrophilic matrix tablets, composed of hydroxypropyl methylcellulose, was studied for seven different polymer batches. A time difference of more than 80h between fully dissolved tablets was noticed although the batches were of the same pharmaceutical substituent (USP 2208) and viscosity (100 cps) grade. To find the functionality related parameters for polymer release from hydrophilic matrix tablets the polymer samples were characterised according to size and chemical composition. The size of the polymers was characterised by size-exclusion chromatography with multi-angle light scattering and refractive index detection. The average amount of substituents was measured with nuclear magnetic resonance and the distribution of the substituents along the cellulose chain was determined with high-performance anion-exchange chromatography with pulsed amperometric detection after acid and enzymatic hydrolysis. The results indicated that other types of interactions apart from entanglements were present between the polymer chains, which seemed to affect the polymer release. Most importantly, this study has shown a correlation between the polymer release and the substituent pattern, where the samples with slow release also were more heterogeneously substituted along the polymer chain. From this we can conclude that polymer release is very sensitive to alterations in chemical composition.


Subject(s)
Methylcellulose/analogs & derivatives , Polymers/chemistry , Tablets , Chromatography, Gel , Hypromellose Derivatives , Magnetic Resonance Spectroscopy , Methylcellulose/chemistry , Molecular Weight
10.
Eur J Pharm Sci ; 36(2-3): 297-309, 2009 Feb 15.
Article in English | MEDLINE | ID: mdl-19038336

ABSTRACT

Four different HPMC batches were characterized to investigate properties related to critical functionality for their use in hydrophilic matrix tablets. In this study, the HPMC batches were chemically characterized and correlated to the behaviour of pure HPMC tablets. Parameters such as the molecular weight, viscosity, intrinsic viscosity and radius of gyration were kept in a rather limited range, which resulted in a weak correlation to polymer release and degree of swelling. The hydrophilic/hydrophobic character of the HPMC samples was elucidated by the degree of substitution and by the clouding behaviour, where an increased hydrophilicity increased the tablet swelling. This phenomenon was interpreted in a refined model for water transport into HPMC tablets. A five times slower polymer release and a considerably larger degree of swelling were found for one batch of HPMC tablets compared to the others, although the characterized average polymer parameters were in the same range. However, the conformation plot displayed a fraction with compact aggregates. In conclusion, the existence of aggregates in aqueous solution seems to perturb the functionality of HPMC tablets and it seems important to understand and characterize these aggregates to fully predict the polymer release and swelling of HPMC tablets.


Subject(s)
Methylcellulose/analogs & derivatives , Tablets/chemistry , Delayed-Action Preparations/chemistry , Excipients/chemistry , Hydrophobic and Hydrophilic Interactions , Hypromellose Derivatives , Light , Methylcellulose/chemistry , Molecular Conformation , Molecular Weight , Nephelometry and Turbidimetry , Particle Size , Porosity , Refractometry , Rheology , Scattering, Radiation , Solubility , Temperature , Tensile Strength , Viscosity , Water/chemistry
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