Duncan Q.M. Craig

The mechanisms of drug release from solid dispersions in water-soluble polymers

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. However, despite the publication of numerous original papers and reviews on the subject, the mechanisms underpinning the observed improvements in dissolution rate are not yet understood. In this review the current consensus with regard to the solid-state structure and dissolution properties of solid dispersions is critically assessed. In particular the theories of carrier- and drug-controlled dissolution are highlighted. A model is proposed whereby the release behaviour from the dispersions may be understood in terms of the dissolution or otherwise of the drug into the concentrated aqueous polymer layer adjacent to the solid surface, including a derivation of an expression to describe the release of intact particles from the dispersions. The implications of a deeper understanding of the dissolution mechanisms are discussed, with particular emphasis on optimising the choice of carrier and manufacturing method and the prediction of stability problems.

The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems

Many pharmaceuticals, either by accident or design, may exist in a total or partially amorphous state. Consequently, it is essential to have an understanding of the physico-chemical principles underpinning the behaviour of such systems. In this discussion, the nature of the glassy state will be described, with particular emphasis on the molecular processes associated with glass transitional behaviour and the use of thermal methods for characterising the glass transition temperature, Tg. The practicalities of such measurements, the significance of the accompanying relaxation endotherm and plasticization effects are considered. The advantages and difficulties associated with the use of amorphous drugs will be outlined, with discussion given regarding the problems associated with physical and chemical stability. Finally, the principles of freeze drying will be described, including discussion of the relevance of glass transitional behaviour to product stability.

An investigation into the rheological, dielectric and mucoadhesive properties of poly(acrylic acid) gel systems

Abstract A range of recently introduced poly(acrylic acid) polymers (Carbopols 974P, 934P and EX-214, Noveon AA-1) have been prepared as 2.5% w/w gels in water using three different neutralising agents: sodium hydroxide, triethanolamine (TEA) and tromethamine (Tris). The structures of the gels were characterised in comparison to unneutralised systems using oscillatory rheology and low frequency dielectric spectroscopy. Rheological evaluation indicated that the elastic moduli of the gels decreased in the rank order Carbopol 934P, 974P, Noveon AA-1 and Carbopol EX-214, with the reverse order being observed for the tan δ values. The effects of changing the neutralising agent were less marked. The dielectric responses showed differences between the various polymers and also between the same polymer with different neutralising agents. In particular, samples neutralised with TEA consistently showed a greater low frequency conductance than gels neutralised with the other agents. This effect was associated with charges being more closely bound into the polymer network in the TEA neutralised gels. It was also noted that the rheological and dielectric behaviour of NaOH neutralised Carbopol 974P was markedly different to that of Carbopol EX-214, despite the supposed equivalence of these two materials. The mucoadhesive properties of the various gels were compared using a force of detachment test. It was shown that Carbopols 934P and 974P showed the greatest mucoadhesive strength, with smaller differences being noted between systems containing the various neutralising agents. A correlation between mucoadhesive strength and rheological tan δ values was observed.

Modulated temperature differential scanning calorimetry: A novel approach to pharmaceutical thermal analysis

Modulated temperature differential scanning calorimetry (MTDSC) is a novel thermoanalytical technique which involves the application of a sinusoidal heating programme to a sample and the resolution of the response into reversing and non-reversing signals, thereby enabling the deconvolution of complex and overlapping thermal processes. This represents an important advance on conventional differential scanning calorimetry (DSC), which involves the use of a linear heating programme, and does not allow the separation of the signal into component responses. In this review, the principles and current uses of conventional DSC will be discussed and compared to those of MTDSC, particularly with a view to emphasising the comparative advantages of the new technique with respect to existing methods. A discussion will be given of how this technique may be applicable to a range of pharmaceutical systems.

Characterisation of solid dispersions of paracetamol and EUDRAGIT E prepared by hot-melt extrusion using thermal, microthermal and spectroscopic analysis.

Hot-melt extrusion has attracted considerable interest within the pharmaceutical industry. However, there remains some uncertainty as to how to characterise the physical structure of the extruded systems, particularly in terms of identifying the nature of the drug dispersion within the polymer. The aim of the study was to develop a combined thermal, imaging and spectroscopic approach for the identification and characterisation of the drug and polymer structure. Solid dispersions containing 10% and 20% paracetamol in EUDRAGIT E were prepared by hot-melt extrusion into elongated strands. Differential scanning calorimetry (DSC) run at scanning rates up to 100 degrees C/min, modulated temperature DSC, microthermal analysis (mu-TA) and Attenuated Reflection Fourier Transform IR (ATR-FTIR) were used to characterise the systems. It was noted that the glass transition of the dispersions were considerably lower than the polymer alone, indicating dispersion of the drug in the polymer on a molecular basis. However, thermal and spectroscopic evidence was also obtained for the presence of crystalline drug at the 10% and 20% loadings, indicating that the drug was present in two physical forms simultaneously. Furthermore, both ATR-FTIR and microthermal analysis indicated that the drug crystals were preferentially located in the centre, rather than on the surface, of the extrudate. The study has indicated that the dispersion of the drug in the polymer may be complex in terms of both physical form and spatial distribution, with potential ramifications for stability and dissolution kinetics. In addition, the investigation has indicated that the combined approach outlined here is highly appropriate, as no single technique may yield all the required information.

A comparison of different in vitro methods for measuring mucoadhesive performance

Abstract The purpose of this study was to assess and compare several in vitro methods for measuring mucoadhesive performance, using a controlled-stress rheometer and a penetrometer (texture analyser). Three poly(acrylic acid) (PAA) polymers, differing in their cross-linking status, were selected, namely Carbopol 974P, Carbopol 971P and Noveon AA-1 (polycarbophil). The polymers were used in two neutralisation states (acidic and neutralised with triethanolamine) and two physical states (hydrogel and compact). The in vitro methods tested were categorised as ‘bulk’ and ‘tensile’. Bulk techniques concerned the structure analysis of polymer gels and polymer/mucin mixtures by oscillatory rheology and penetrometry. Rheological synergy, dependent on the frequency of oscillation, was detected in the case of neutralised PAA/mucin mixtures, as opposed to unneutralised mixtures, where only a decrease in elasticity were found. A linear relationship was found between the phase angle δ and the area under the penetration/withdrawal curve when samples of similar structure were examined. The tensile methods involved the assessment of maximum detachment force and work of adhesion between polymer gels (or compacts) and a layer of 30% mucin gel. In the case of compacts, the hydration time was varied from 1 to 20 min and was found to affect the mucoadhesive performance. The tensile methods detected differences in mucoadhesive properties among the three structurally similar polymers, giving the same rank order as was found for the rheological properties.

Characterization of the Block Structure and Molecular Weight of Sodium Alginates

Sodium alginates are widely used within the pharmaceutical sciences, yet the molecular characteristics of these materials are frequently not stated. In this study, a range of characterization techniques is applied to five sodium alginate samples and the data compared, both between techniques and with the information obtained from the manufacturer.

An investigation into the effects of residual water on the glass transition temperature of polylactide microspheres using modulated temperature DSC.

The objective of the study was to ascertain residual water levels in polylactide and polylactide-co-glycolide microspheres prepared using the solvent evaporation technique and to investigate the effects of that water on the glass transitional behaviour of the microspheres. Microspheres were prepared from polylactic acid (PLA) and polylactide-co-glycolide (PLGA) 50:50 and 75:25 using a standard solvent evaporation technique. The glass transition was measured as a function of drying conditions using modulated temperature DSC. The microspheres were found to contain very low levels of dichloromethane, while residual water levels of up to circa 3% w/w were noted after freeze or oven drying, these levels being higher for microspheres containing higher glycolic acid levels. The residual water was found to lower the T(g) following the Gordon-Taylor relationship. The data indicate that the microparticles may retain significant water levels following standard preparation and drying protocols and that this drying may markedly lower the T(g) of the spheres.

Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings.

The in vitro release characteristics of eight low-molecular-weight drugs (clindamycin, 17beta-estradiol, 17beta-estradiol-3-acetate, 17beta-estradiol diacetate, metronidazole, norethisterone, norethisterone acetate and oxybutynin) from silicone matrix-type intravaginal rings of various drug loadings have been evaluated under sink conditions. Through modelling of the release data using the Higuchi equation, and determination of the silicone solubility of the drugs, the apparent silicone elastomer diffusion coefficients of the drugs have been calculated. Furthermore, in an attempt to develop a quantitative model for predicting release rates of new drug substances from these vaginal ring devices, it has been observed that linear relationships exist between the log of the silicone solubility of the drug (mg x ml(-1)) and the reciprocal of its melting point (K(-1)) (y=3.558x-9.620, R=0.77), and also between the log of the diffusion coefficient (cm(2) s(-1)) and the molecular weight of the drug molecule (g x mol(-1)) (y=-0.0068x-4.0738, R=0.95). Given that the silicone solubility and silicone diffusion coefficient are the major parameters influencing the permeation of drugs through silicone elastomers, it is now possible to predict through use of the appropriate mathematical equations both matrix-type and reservoir-type intravaginal ring release rates simply from a knowledge of drug melting temperature and molecular weight.

An investigation into the structure and bioavailability of α-tocopherol dispersions in Gelucire 44/14

In this investigation we describe the preparation, physical characterisation and in vivo behaviour of solid dispersions of a liquid nutraceutical, alpha-tocopherol, in Gelucire 44/14 with a view to establishing whether dispersion in this matrix may provide a means of formulating a liquid drug in a solid dosage form while also improving the oral bioavailability. Using Vitamin E Preparation USP as the source of alpha-tocopherol, dispersions were prepared using a melt-fusion method with active loadings up to 50% (w/w) and characterised using differential scanning calorimetry and optical microscopy. Capsules containing 300 IU alpha-tocopherol were manufactured and the absorption profiles compared to a commercial soft gelatin capsule preparation in healthy human volunteers. Confocal laser scanning microscopy (CLSM) studies were performed in order to elucidate the mechanism by which drug release may be occurring. Differential scanning calorimetry studies indicated that the presence of the active had a negligible effect on the melting profile of the carrier, indicating limited miscibility between the two components, a conclusion supported by the microscopy studies. Similarly, the dispersions were shown to exhibit a glass transition corresponding to the incorporated drug, indicating molecular cooperativity and hence phase separation from the lipid base. Despite the phase separation, it was noted that capsules stored for 18 months under ambient conditions showed no evidence of leakage. Bioavailability studies in six healthy male volunteers indicated that the Gelucire 44/14 formulation showed an approximately two-fold increase in total alpha-tocopherol absorption compared to the commercial preparation. Confocal laser scanning microscopy studies indicated that, on contact with water, the dispersions formed two interfacial layers, from which the Gelucire 44/14 disperses in the liquid medium as small particles. Furthermore, evidence was obtained for the dispersed material becoming incorporated into the hydrated lipid. In conclusion, the dispersion of the liquid drug in Gelucire 44/14 appears to allow the dual advantages of the preparation of a solid formulation and improved bioavailability of this material.