Microstructural Elucidation of Self-Emulsifying System: Effect of Chemical Structure

Purpose

Self-emulsifying systems (SES) emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase. The self-emulsification process plays an important role during formation of emulsion. The objective of current work was to understand and explore the inner structuration of SES through controlled hydration and further to study the influence of additive on the same which ultimately governs performance of final formulation in terms of droplet size.

Methods

Droplet size of final formulations containing structural analogues of ibuprofen was determined. Microstructural properties of intermediate hydrated regimes of SES were investigated using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology.

Results

The current work established inverse relationship between droplet size of the formulations containing structural analogues of ibuprofen and their Log P values. Microstructural analysis of intermediate hydrated regimes of the prepared samples showed formation of local lamellar structure. Structural analogues of ibuprofen significantly altered microstructure of lamellae which was well correlated with the droplet size of final formulations. In vitro drug release study showed increase in dissolution rate of lipophillic drugs when formulated as SES.

Conclusion

The current work emphasizes the fact that tailor-made formulations can be prepared by controlling the properties of intermediate regimes.

Mapping Ion-Induced Mesophasic Transformation in Lyotropic In Situ Gelling System and its Correlation with Pharmaceutical Performance

Purpose

To investigate influence of ion induced mesophasic transformation on pharmaceutical performance of in situ gelling system consisting of glyceryl monooleate.

Methods

The prepared system showed mesophasic transformation during its conversion from sol to gel upon controlled hydration. The process of mesophasic transformation was studied by SAXS, DSC, rheology and plane polarized light microscopy. Further the influence of additives i.e. naproxen salts (sodium and potassium) and naproxen (base) on the process of mesophasic transformation was also elucidated.

Results

It was observed that addition of salt form of naproxen transformed W/O emulsions into cubic mesophase whereas addition of base form of naproxen formed reverse hexagonal (H_II) phase upon controlled hydration. The cubic mesophase formed by naproxen salts retarded the drug release for initial 3 h whereas H_II phase showed sustained drug release characteristics for naproxen base following Higuchi drug release kinetics.

Conclusion

The current work suggests that formulations with tailor made pharmaceutical performance can be developed by selecting proper additives in the system so as to obtain the desired mesophase ‘on demand’ thereby controlling drug release characteristics.

Correlation between drug release kinetics from proteineous matrix and matrix structure: EPR and NMR study

The present study was conducted in order to probe the microstructure, microviscosity, and hydration properties of matrices containing two model drugs, naproxen sodium (NS) and naproxen (N), and egg albumin (EA) as matrix carrier. The results suggested that N release from EA matrix was controlled by a bulk erosion mechanism in combination with additional processes (crystal dissolution/crystallization rate) compared with NS matrix, which behaved as a non-erodible matrix and drug release occurred by diffusion through the gel. Using EPR technique it has been shown that incorporating NS into EA matrix strongly influences the microstructure of the protein gel, and hence the transport of the penetrant within the matrix, compared with matrices containing N. The presence of NS increased the protein chain mobility and hydration which supports our previous results showing that NS cause unfolding of EA. In contrast, N caused only marginal effect on EA chain mobility. The gel formed in EA/NS matrices was more porous compared with EA/N matrices as revealed by the lower rotational correlation time of PCA (lower microviscosity) in EA/NS matrices compared with EA/N. However, EA/N gelled matrices were more heterogeneous, i.e., containing a higher number of components having different mobility. The T(1) and T(2) relaxation studies by NMR provided an additional support for the higher chain hydration in EA/NS matrices compared with EA/N as indicated by the higher relaxation rates in the gelled matrices. Internal pH measurements by EPR revealed that the micro-pH inside 100% EA and 50/50 EA/N matrices were lower than 50/50 EA/NS matrices and in all cases lower than the penetrating buffer pH. The lower pH compartment formed in N matrices affected N solubility and crystal dissolution rate, which can explain its lower release rate compared with EA, from the same formulation. The EPR and NMR data supports our findings that NS caused unfolding of the protein, affected matrix structure, and converted it to a hydrophobic non-erodible matrix compared with EA/N matrix in which the native properties of EA were mainly retained.     

A topical dosage form of liposomal clofazimine: research and clinical implications

A novel topical clofazimine (CLO) gel formulation containing liposomally encapsulated CLO, was prepared and investigated in vitro followed by a clinical evaluation. CLO liposomes were prepared by the lipid film hydration technique. Comparative in vitro diffusion studies were conducted with plain and liposomal CLO in HPMC K4M gel base (2% and 5%) using human cadaver skin (HCS). A double blind clinical study was conducted on eight leprosy patients. The results of these studies show that the new liposomal topical gel formulation not only prolongs the drug release but also promotes drug retention by the skin. Studies further support formation of a reservoir of drug on the skin modifying therapeutic efficacy of the formulation. The new liposomal gel formulation of CLO considerably reduces the healing time of external lesions due to a significantly prolonged skin residence time compared to plain CLO gel and hence is expected to reduce the time needed for leprosy treatment.     

5-Fluorouracil in topical liposome gels for anticancer treatment--formulation and evaluation

Liposome gels bearing an antineoplastic agent, 5-fluorouracil, intended for topical application have been prepared and drug release properties in vitro have been evaluated. Different formulations of liposomes were prepared by the film hydration method by varying the lipid phase composition (PL 90H/cholesterol mass ratio) and hydration conditions of dry lipid film (drug/aqueous phase mass ratio). Topical liposome gels were prepared by incorporation of lyophilized liposomes into a structured vehicle (1%, m/m, chitosan gel base). Also, hydrogels containing different concentrations of 5-fluorouracil were prepared and drug release properties were investigated. The rate of drug release from liposome gels was found to be dependent on the bilayer composition and the dry lipid film hydration conditions. Also, liposomes embedded into a structured vehicle of chitosan showed significantly slower release than hydrogels. The drug release obeyed the Higuchi diffusion model, while liposomes acted as reservoir systems for continuous delivery of the encapsulated drug.     

Development of lamellar gel phase emulsion containing baru oil (Dipteryx alata Vog.) as a prospective delivery system for cutaneous application

The rational design of emulsions requires study of the main factors that influence their formation, physicochemical properties and, consequently, stability and performance. The use of vegetable oils in the pharmaceutical and cosmetic industries has recently become attractive. Dipteryx alata Vogel (D. alata) is an oleaginous species native to Brazil. The seeds of this species contain highly unsaturated oil with significant amounts of tocopherols and phytosterols, representing an important source of agents capable of combatting oxidative processes. In this work, a lamellar gel phase emulsion using oil extracted from the seeds of D. alata (baru) was developed. The steps involved in the development of this research were as follows: 1) development of formulations and 2) in vitro assays by simulating the evaporation of the final product after application to the skin and Electron paramagnetic resonance spectroscopy (EPR) of fatty acid spin labels was used to investigate the profile of interaction of the dispersed systems with stratum corneum (SC) lipids. The results indicate that the developed system shows no signs of instability during the storage period. Moreover, EPR studies indicated that D. alata oil and especially the developed formulation were able to increase SC lipid fluidity and extract a fatty-acid spin label from the lipid domain structures of SC, demonstrating its potential to act as a drug or skin care vehicle.     

Characterization of the effects of drug addition on the structure of glyceryl monoolein/water gel systems using low frequency dielectric spectroscopy.

The influence of propantheline bromide incorporation on the phase structure of glyceryl monoolein/water systems has been investigated using low-frequency dielectric spectroscopy over a frequency range of 10(-2) to 10(6) Hz at 20 degrees C. The responses of glyceryl monoolein systems composed of 10% and 30% w/w were measured and the spectra modeled using an equivalent circuit based on the Maxwell-Wagner theory.1,2 Marked changes in the dielectric responses of the systems were noted on addition of the propantheline bromide at concentrations up to 10% w/w. For the lamellar (10% w/w water) glyceryl monoolein systems, an increase in the imaginary permitivity was seen, corresponding to an increase in conductivity due to the presence of additional ionic species within the system. Evidence was also obtained for the incorporation of the drug directly into the lipid bilayers, particularly at higher concentrations (10% drug) at which dielectric behavior corresponding to bilayer disruption was seen. Incorporation of 3% and 5% w/w drug into the cubic phase systems (30% w/w water) resulted in a change to the lamellar phase. However, circuit modeling indicated that the system formed structures which showed features of both the lamellar and cubic phases at 3% w/w drug loadings. The study has therefore demonstrated that dielectric analysis may provide a novel means of studying the effects of drug incorporation on the phase behavior of complex gel systems.     

Synchrotron X-ray investigations into the lamellar gel phase formed in pharmaceutical creams prepared with cetrimide and fatty alcohols

Semisolid liquid paraffin-in-water emulsions (aqueous creams) prepared from cetrimide/fatty alcohol mixed emulsifiers, and ternary systems formed by dispersing the mixed emulsifier in controlled percentages of water were examined as they aged using a combination of low and high angle X-ray diffraction measurements (Daresbury Laboratory Synchrotron Radiation Source). The results were correlated with the rheological properties measured in earlier studies. The cationic emulsifying wax showed phenomenal swelling in water. The reflection that incorporates interlamellar water increased continuously from 74 A at 28% water to over 500 A at 93% water. The trend was not influenced by the method of incorporation of the components and swollen lamellar phase was also identified in the corresponding emulsion. The swelling, which was due to electrostatic repulsion, was suppressed by salt and was reduced when the surfactant counterion was changed from Br(-) to Cl(-). Changes in rheological properties on storage and in the presence of salt were correlated with changes in water layer thickness. High angle diffraction confirmed that the hydrocarbon bilayers were in the hexagonal alpha-crystalline mode of packing. Ternary systems and creams prepared from pure alcohols, although initially semisolid, were rheologically unstable and broke down. Low angle X-ray study into the kinetics of structure breakdown showed that the swollen lamellar gel phase formed initially swells even further on storage before separating.     

Structural Development of Self Nano Emulsifying Drug Delivery Systems (SNEDDS) During <Emphasis Type="BoldItalic">In Vitro</Emphasis> Lipid Digestion Monitored by Small-angle X-ray Scattering

Purpose To investigate the structural development of the colloid phases generated during lipolysis of a lipid-based formulation in an in vitro lipolysis model, which simulates digestion in the small intestine. Materials and Methods Small-Angle X-Ray scattering (SAXS) coupled with the in vitro lipolysis model which accurately reproduces the solubilizing environment in the gastrointestinal tract and simulates gastrointestinal lipid digestion through the use of bile and pancreatic extracts. The combined method was used to follow the intermediate digestion products of a self nano emulsified drug delivery system (SNEDDS) under fasted conditions. SNEDDS is developed to facilitate the uptake of poorly soluble drugs. Results The data revealed that a lamellar phase forms immediately after initiation of lipolysis, whereas a hexagonal phase is formed after 60 min. The change of the relative amounts of these phases clearly demonstrates that lipolysis is a dynamic process. The formation of these phases is driven by the lipase which continuously hydrolyzes triglycerides from the oil-cores of the nanoemulsion droplets into mono- and diglycerides and fatty acids. We propose that this change of the over-all composition of the intestinal fluid with increased fraction of hydrolyzed nanoemulsion induces a change in the composition and effective critical packing parameter of the amphiphilic molecules, which determines the phase behavior of the system. Control experiments (only the digestion medium) or the surfactant (Cremophor RH 40) revealed the formation of a lamellar phase demonstrating that the hexagonal phase is due to the hydrolysis of the SNEDDS formulation. Conclusions The current results demonstrate that SAXS measurements combined with the in vitro dynamic lipolysis model may be used to elucidate the processes encountered during the digestion of lipid-based formulations of poorly soluble drugs for oral drug delivery. Thus the combined methods may act as an efficient screening tool.     

Influence of crystal hydration on the mechanical properties of sodium naproxen.

The aim of this work is to establish a correlation between water uptake by anhydrous sodium naproxen (ASN) at two different relative humidities and modifications in tableting and densification behaviour under hydration. Water uptake was evaluated at different relative humidities. Models for the hydration kinetics of ASN at 55% and 86%, corresponding to the formation of the dihydrated and tetrahydrated forms, respectively, were evaluated assuming Eyring's dependence on temperature. Tabletability, compressibility, compactibility, and densification behaviour were determined using an instrumented single punch tablet machine. Kinetic data are consistent with a model where water molecules enter the crystal preferentially along hydrophilic tunnels existing in the crystal structure and corresponding to the propionate side chain. Water inclusion perturbs the crystallographic structure, causing slight structural changes according to the amount and associated to an increase in entropy. The interposition of water molecules between sodium naproxen molecules weakens intermolecular bonds, and these sites can behave like sliding planes under compression. Such structural changes may explain the improved compression behaviour and modified densification propensity mechanism. Kinetic data describing the water hydration mechanism of ASN explain in an original way the improved tableting and densification properties under hydration.     

Effects of the anti-neoplastic agent ET-18-OCH3 and some analogs on the biophysical properties of model membranes

The effect of 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH(3), edelfosine), and six other analog asymmetric phosholipids on the physical properties of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) model membranes was studied using differential scanning calorimetry (DSC), (31)P-nuclear magnetic resonance ((31)P NMR) and X-ray diffraction. DSC data revealed that, at concentrations of 40mol% and higher, a new type of mixtures with higher T(c) and narrower transitions appeared with all the asymmetric lipids studied. At very high concentrations of these lipids (50-80 mol%), destabilization was observed in the systems probably because of the formation of micelles or small vesicles. In all cases, the asymmetric lipids at concentrations of 40 mol% induced the formation of interdigitated structures in the lamellar gel phase, as deduced from X-ray diffraction. The asymmetric phospholipids were also added to 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (DEPE) model membranes and DSC data revealed that the lipids primarily affected transition from the lamellar gel (L(beta)) to the lamellar liquid crystalline (L(alpha)) phase in two aspects: the transition temperature was reduced, and the transition itself became broader and smaller. The lamellar liquid crystalline (L(alpha)) to inverted hexagonal phase (H(II)) transition was also affected, as detected by DSC and (31)P NMR data. Increasing concentrations of the asymmetric lipids reduced the formation of inverted hexagonal phases, which were completely inhibited in the case of ET-18-OCH(3). Since these compounds have been shown to have important biological actions through the plasma membrane, these results may help to understand the mechanism of action of these compounds. In addition these asymmetric lipids were tested for their capacity to induce cell apoptosis, and only ET-18-OCH(3) was found to have a clear effect, thus suggesting that the apoptotic effect is not exerted through changes in the biophysical properties of model membranes.     

Cationic cage-like complexes formed by DC-cholesterol, Quil-A, and phospholipid

This study describes the formation of cationic, cage-like complexes which have a structure similar to classic anionic ISCOMs. In order to prepare these complexes cholesterol, a major component of classic ISCOM formulations, was substituted with a cationic derivative, 3beta-[N-(N',N'-dimethylaminoethane)-carbamoyl]-cholesterol (DC-CHOL). Colloidal dispersions with varying compositions of DC-CHOL, phosphatidylcholine, and Quil-A, which is a mixture of anionic triterpene saponins, were prepared by the lipid-film hydration method and characterised by transmission electron microscopy and laser Doppler electrophoresis. The colloidal structures obtained are presented in pseudo-ternary phase diagrams with two buffer systems as the pseudo-component. It was found that the formation of cationic, cage-like particles is highly depending on the formulation buffer. With TRIS buffered saline (TBS) pH 7.4, cage-like particles formed at compositions with high proportions of DC-CHOL and had a strongly positive zeta-potential. These could be purified by differential centrifugation. With phosphate buffered saline pH 7.4, the formation of cage-like particles was much reduced. It was shown that the formation of cage-like particles with a positive charge depended on suitable concentrations of TRIS in the hydration buffer.     

Enhancement of percutaneous absorption of naproxen by phospholipids

The skin penetration of naproxen from various phospholipid gel formulations through human cadaver skin was investigated in diffusion chambers. Presence of phospholipids decreased the skin penetration of naproxen from aqueous gels. The addition of 32% (m/m) ethanol or propylene glycol in the aqueous gel formulation, with the presence of phospholipids, apparently increased the percutaneous absorption of naproxen. The penetration enhancement effect of phospholipid with ethanol was, however, more significant than that of phospholipid with propylene glycol. The effect of ethanol concentration on the ability of phospholipids to increase penetration of naproxen, was evaluated in pretreatment studies. The results showed that more than 8% (m/v) ethanol is needed for the enhancing effect of phospholipids. The concentration of phospholipid and the presence of unsaturated fatty acids in phospholipids are also important factors affecting the transdermal flux of naproxen. In conclusion, in the presence of cosolvent, phospholipids increase the transdermal flux of naproxen.     

Rheological and dielectric characterization of monoolein/water mesophases in the presence of a peptide drug

A series of glyceryl monoolein/water gel systems containing 10%, 22%, and 30% w/w water has been investigated using two complementary techniques, oscillatory rheology and dielectric analysis, in order to establish the utility of these two techniques in conjunction and to investigate the influence of the inclusion of a model peptide, cyclosporin A, on the properties of the gels. Oscillatory rheology was performed in two modes; frequency sweeps at 20, 37, and 70 degrees C and temperature sweeps from 20 to 70 degrees C. Dielectric spectroscopy was performed in the kHz to mHz frequency range over a temperature range of 20-70 degrees C. Both rheology and dielectric spectroscopy were able to identify structural changes in the systems analyzed, with the 10% and 30% (w/w) water sample showing typical features of the lamellar and cubic phase respectively at 20 degrees C, while the 22% (w/w) system showed intermediate behavior. The thermotropic phase transitions could be monitored using rheological temperature sweeps. Drug loading resulted in marked changes in rheological and dielectric response of the 10% w/w water system, causing a decrease in both elasticity and permittivity values, while a less marked effect was observed for the 22% and, in particular, the 30% w/w systems. The investigation has demonstrated that rheological and dielectric measurements yield distinct yet complementary information and that the inclusion of a model peptide may alter the properties of the gel, the extent of the effect being dependent on the phase composition of the system.     

Effect of HLB of additives on the properties and drug release from the glyceryl monooleate matrices.

Glyceryl monooleate (GMO) is an amphiphilic surfactant, which as such can solubilize hydrophilic, lipophilic and amphiphilic drug molecules in its different polarity regions. Addition of additives with different polarities in GMO leads to change in phase behavior and related properties of GMO. Effect of the additives with different hydrophilic lipophilic balance (HLB; 1.5, 3, 4, 5, 7, 10 and 11) in GMO matrices on its phase transformation, rheological properties, mechanical properties, wetting and release behavior was investigated. Polarizing light microscopy showed that the GMO matrices incorporated with lower HLB additive (1.5, 3, 4 and 5) form cubic phase at higher rate while lamellar phase was prominent for matrices with additive of HLB 7, 10 and 11. The diametrical crushing strength and viscosity was decreased with increased HLB of additive. Lower HLB additives enhanced contact angle as compared to plain matrices and high HLB additives induced change in solid-liquid interface from hydrophobic to hydrophilic leading to decline in contact angle. Percent swelling of matrices was increased linearly with increase in HLB of additives. Tensiometric method was used for determination of bioadhesive strength of hydrated matrices and it was observed that matrices with additives of HLB 10 presented highest bioadhesion due to higher rate of hydration and formation of lamellar phase. As the HLB of additives in matrix increased, release was shifted from anomalous (non-Fickian) diffusion and/or partially erosion-controlled release to Fickian diffusion. Initial lag was observed for drug released from matrices with additive of HLB 1.5, 3, 4 and 5. Thus incorporation of the additives of different HLB changed molecular packing, which significantly affected drug release pattern.     

Factors affecting the formation of eutectic solid dispersions and their dissolution behavior

The objective of this work was to obtain a fundamental understanding of the factors, specifically the properties of poorly water-soluble drugs and water-soluble carriers, which influence predominantly, the formation of eutectic or monotectic crystalline solid dispersion and their dissolution behavior. A theoretical model was applied on five poorly water-soluble drugs (fenofibrate, flurbiprofen, griseofulvin, naproxen, and ibuprofen) having diverse physicochemical properties and water-soluble carrier (polyethylene glycol (PEG) 8000) for the evaluation of these factors. Of these, two drugs, fenofibrate and flurbiprofen, and PEG of different molecular weights (3350, 8000, and 20000), were chosen as model drugs and carriers for further investigation. Experimental phase diagrams were constructed and dissolution testing was performed to assess the performance of the systems. The theoretical model predicted the formation of eutectic or monotectic solid dispersions of fenofibrate, griseofulvin, ibuprofen, and naproxen with PEG, holding the contribution of specific intermolecular interactions between compound and carrier to zero. In the case of the flurbiprofen-PEG eutectic system, intermolecular interactions between drug and polymer needed to be taken into consideration to predict the experimental phase diagram. The results of the current work suggest that the thermodynamic function of melting point and heat of fusion (as a measure of crystal energy of drug) plays a significant role in the formation of a eutectic system. Lipophilicity of the compound (as represented by cLog P) was also demonstrated to have an effect. Specific interactions between drug and carrier play a significant role in influencing the eutectic composition. Molar volume of the drug did not seem to have an impact on eutectic formation. The polymer molecular weight appeared to have an impact on the eutectic composition for flurbiprofen, which exhibits specific interactions with PEG, whereas no such impact of polymer molecular weight on eutectic composition was observed for fenofibrate, which does not exhibit specific interactions with PEG. The impact of polymer molecular weight on dissolution of systems where specific drug-polymer interactions are exhibited was also observed. The current work provides valuable insight into factors affecting formation and dissolution of eutectic systems, which can facilitate the rational selection of suitable water-soluble carriers.     

Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance

In this study, pectinate gel beads were produced by ionotropic gelation method with different solutions of cross-linking agents and ketoprofen was entrapped as model drug. The influence of these formulation parameters was investigated upon bead properties and upon their performance to target the colon. Zinc pectinate beads obtained with 10% of counter-ions solution at pH 1.6 exhibited the strongest gel network due to "egg-box" dimmer formation helped by hydrogen bonding. Furthermore the gel network formed at low pH was arranged in a compact three-fold conformation. Thus, this matrix structure in enteric capsules induced the lowest drug release in the upper gastro-intestinal tract (pH 1.2 following by pH 7.4). However ketoprofen release occurred specifically in the colon thanks to the presence of pectinolytic enzymes and the release rate can be modulated by the counter-ion concentration during the reticulation process. Therefore this approach using pectinate beads is very promising as efficient carrier for specific delivery of drug into the colon, after oral administration.     

Design, development and optimization of nimesulide-loaded liposomal systems for topical application

Nimesulide, a non-steroidal anti-inflammatory drug, was incorporated into multilamellar liposomes to improve its performance on topical administration. The drug was loaded onto liposomes employing thin film hydration technique. Various process and formulation variables were investigated to obtain the liposomal products of desired quality. Liposomes were monitored for percent drug entrapment, after separating the unentrapped drug by mini column centrifugation, for vesicular properties (such as size distribution profile, morphological attributes and agglomeration tendency), drug diffused through synthetic semipermeable membrane, and drug leakage. Systematic optimization studies were carried out using 3(2) factorial design to select the optimized liposomal composition with reference to percent drug entrapment, drug diffusion and leakage. The optimized batch of liposomes was subjected to drug permeation and drug retention studies employing rat skin and human cadaver skin. In comparison to methanolic solution of pure nimesulide, liposomal formulations were found to retain higher amounts of nimesulide in the skin. Anti-inflammatory studies, using carragenan-induced rat paw edema model, indicated significantly better performance of liposomally entrapped nimesulide in comparison to the marketed gel formulation and the Carbopol gel containing nimesulide.     

Microstructural imaging of early gel layer formation in HPMC matrices

A real-time confocal fluorescence imaging method has been developed which allows the critical early stages of gel layer formation in hydroxypropylmethylcellulose (HPMC) matrices to be examined. Congo Red, a fluorophore whose fluorescence is selectively intensified when bound to beta-D-glucopyranosyl sequences, has allowed mapping of hydrated polymer regions within the emerging gel layer, and revealed for the first time, the microstructural sequence of polymer hydration during development of the early gel layer. Liquid penetration and swelling can be examined in unprecedented detail. The earliest images revealed an initial phase of liquid ingress into the tablet pore network, followed by the progressive formation of a coherent gel layer by outward columnar swelling and coalescence of hydrated HPMC particles. Salts can markedly affect HPMC matrix behaviour. Gel layer growth in 0.1-0.5 M NaCl was progressively suppressed until at 0.75 M, particles clearly failed to coalesce into a gel layer, although with considerable polymer swelling. The failure to form a limiting diffusion barrier resulted in enhanced liquid penetration of the core, and the swelling of particles that did not coalesce culminated in surface disintegration. This provides direct evidence of physical mechanisms that contribute to salts accelerating drug release from HPMC matrices.