Investigating the Structure and properties of Hydrated Hydroxypropyl methylcellulose and Egg Albumin Matrices Containing Carbamazepine: EPR and NMR Study

Purpose. The present study was conducted in order to investigate the correlation between the hydration properties of HPMC and EA matrices, gel microstructure and mobility, crystalline changes occurring in the gel and CBZ release kinetics. The influence of HPMC and EA erosion modes on CBZ release kinetics was interpreted in terms of gel microstructures. Methods. NMR technique was used to determine the T ₁ and T ₂ relaxation rates of water in hydrated matrices. PFGSE NMR technique was employed to determine the SDC of water in the gels. EPR technique was used to determine the rotational correlation time of PCA in the hydrated matrices, gel microviscosity, mobile compartment, , , parameters and lorentzian/ gaussian ratio. These parameters are indicative of matrix microstructure. Results. CBZ release mechanism from HPMC and EA matrices was markedly different. This behavior was related to the different structures of the polymer and protein. T ₂ relaxation studies and SDC measurements by NMR revealed higher chain hydration for HPMC compared to EA. Using the EPR technique it has been shown that the microviscosity and mobile compartment of matrices containing HPMC are lower than matrices containing EA. The microviscosity, mobile compartment and S-parameter values of hydrated matrices containing different EA/CBZ ratios were in correlation with the crystallization properties of CBZ in the gels, matrix erosion properties and CBZ release kinetics from the matrices. Conclusions. Characterization of matrix structures using EPR and NMR techniques supported our hypothesis concerning the mechanism involved in HPMC-CBZ interaction. EA/CBZ matrix microstructure features, analyzed by NMR and EPR techniques, were in correlation with the crystalline changes occurring in the gel and drug release kinetics.     

Correlation between the viscoelastic properties of the gel layer of swollen HPMC matrix tablets and their in vitro drug release

Abstract

Drug release from hydroxypropyl methylcellulose (HPMC) hydrophilic matrix tablets is controlled by drug diffusion through the gel layer of the matrix-forming polymer upon hydration, matrix erosion or combination of diffusion and erosion mechanisms. In this study, the relationship between viscoelastic properties of the gel layer of swollen intact matrix tablets and drug release was investigated. Two sets of quetiapine fumarate (QF) matrix tablets were prepared using the high viscosity grade HPMC K4M at low (70?mg/tablet) and high (170?mg/tablet) polymer concentrations. Viscoelastic studies using a controlled stress rheometer were performed on swollen matrices following hydration in the dissolution medium for predetermined time intervals. The gel layer of swollen tablets exhibited predominantly elastic behavior. Results from the in vitro release study showed that drug release was strongly influenced by the viscoelastic properties of the gel layer of K4M tablets, which was further corroborated by results from water uptake studies conducted on intact tablets. The results provide evidence that the viscoelastic properties of the gel layer can be exploited to guide the selection of an appropriate matrix-forming polymer, to better understand the rate of drug release from matrix tablets in vitro and to develop hydrophilic controlled-release formulations.     

The Effect of Excipients on the Molecular Mobility of Lyophilized Formulations,as Measured by Glass Transition Temperature and NMR Relaxation-Based Critical Mobility Temperature

Purpose. The dependence of the molecular mobility of lyophilized formulations on pharmaceutical polymer excipients was studied. Molecular mobility as determined by NMR relaxation-based critical temperature of molecular mobility (T_mc) and glass transition temperature (T_g) is discussed in relation to the plasticizing effect of water in formulations. Methods. The T_mc and T_g of lyophilized -globulin formulations containing 6 different polymer excipients such as dextran, polyvinylpyrrolidone (PVP) and methylcellulose (MC) was determined by NMR and DSC. The molecular mobility of water in the formulations was determined by proton NMR and dielectric relaxation spectrometry (DRS). Results. T_mc varied with polymer excipients. T_mc increased as the ratio of bound water to mobile water increased and as the molecular mobility of mobile water decreased. The formulation containing MC exhibited a lower T_mc than the formulation containing dextran because of the smaller ratio of bound water and the higher molecular mobility of mobile water. The T_mc of the formulation containing PVP was higher than that expected from the higher T₂ values of water because of the lower molecular mobility of mobile water regardless of the higher ratio of mobile water. The T_mc of these lyophilized formulations was higher than their T_g by 23°C to 34°C, indicating that the formulations became a NMR-detected microscopically liquidized state below their T_g. Conclusions. The quantity and the molecular mobility of mobile water in lyophilized formulations can be considered to affect the T_mc of lyophilized formulations, which in turn governs their stability.     

Magnetic Resonance Microscopy for Assessment of Morphological Changes in Hydrating Hydroxypropylmethyl Cellulose Matrix Tablets In Situ

Purpose

To resolve contradictions found in morphology of hydrating hydroxypropylmethyl cellulose (HPMC) matrix as studied using Magnetic Resonance Imaging (MRI) techniques. Until now, two approaches were used in the literature: either two or three regions that differ in physicochemical properties were identified.

Methods

Multiparametric, spatially and temporally resolved T₂ MR relaxometry in situ was applied to study the hydration progress in HPMC matrix tablets using a 11.7 T MRI system. Two spin-echo based pulse sequences—one of them designed to specifically study short T₂ signals—were used.

Results

Two components in the T₂ decay envelope were estimated and spatial distributions of their parameters, i.e. amplitudes and T₂ values, were obtained. Based on the data, five different regions and their temporal evolution were identified: dry glassy, hydrated solid like, two interface layers and gel layer. The regions were found to be separated by four evolving fronts identified as penetration, full hydration, total gelification and apparent erosion.

Conclusions

The MRI results showed morphological details of the hydrating HPMC matrices matching compound theoretical models. The proposed method will allow for adequate evaluation of controlled release polymeric matrix systems loaded with drug substances of different solubility.     

The effect of HPMC—a cholesterol-lowering agent—on oral drug absorption in dogs

The objective of this study was to evaluate the effects which hydroxypropylmethylcellulose (HPMC) may exert on oral drug absorption, in cases where this soluble fiber is administered to regulate blood lipid levels. Studies were conducted in vitro and in healthy female mongrel dogs using two different grades of HPMC, i.e. K8515 HPMC and ultra high molecular weight (UHMW) HPMC. The maximum plasma concentration, C_max, of paracetamol and both the C_max and the area under the concentration–time curve, AUC, of cimetidine were significantly decreased by the coadministration of 10 g of K8515 HPMC or 7.5 g of UHMW HPMC dissolved in 500 mL normal saline under fasting conditions. No statistically significant effects were observed on hydrochlorothiazide or mefenamic acid absorption. Based on in vitro data and previous studies it appears that reductions in gastric emptying and dissolution rate of paracetamol account for the effect observed in vivo. For cimetidine, a drug which can be absorbed from both the small and the large intestine, the indigestibility of HPMC in the colon in addition to the great reduction of dissolution rate led to reductions of both the C_max and AUC values. The long T_max values, even in the absence of HPMCs and the more modest reduction of the dissolution rate of hydrochlorothiazide by the HPMCs are thought to have precluded the observation of any significant alterations in the in vivo absorption profile. Owing to its erratic absorption, no statistically based conclusion could be drawn about the effects of coadministered HPMC on the oral absorption of the poorly soluble mefenamic acid. It is concluded that the effects of HPMCs on drug absorption in dogs are most pronounced for compounds with absorption profiles that are dependent on gastric emptying, i.e. compounds that are highly water soluble and that exhibit short T_max values. Compounds with long absorption profiles appear to be less susceptible to changes in absorption behavior due to coadministration of HPMCs. Copyright © 1998 John Wiley & Sons, Ltd.     

Molecular Mobility in Mixtures of Absorbed Water and Solid Poly(vinylpyrrolidone)

Poly(vinylpyrrolidone) (PVP) was used as model system to examine molecular mobility in mixtures of absorbed water with solid amorphous polymers. Water vapor absorption isotherms were determined, along with diffusion and proton NMR relaxation measurements of absorbed water. Concurrently, measurements of glass transition temperatures (T _g) and carbon-13 NMR relaxation times for PVP were determined as a function of water content. Two water contents were used as reference points: W _m, obtained from the fit of water absorption isotherms to the BET equation, corresponding to the first shoulder in the sigmoid isotherm; and W _g, the amount of water necessary to depress T _g to the isotherm temperature. Translational diffusion coefficients of water, along with proton T ₁ relaxation time constants, show that both the translational and the rotational mobility of the water is hindered by the presence of the solid polymer and that the absorbed water is most likely represented by two or more populations of water with different modes or time scales of motion. The presence of "tightly bound or immobilized water at levels corresponding to W _m, however, is unlikely, since water molecules maintain a high degree of mobility, even at the lowest levels of water. Above W _g, water shows an increase in mobility with increasing water content, but it is always less mobile than bulk water. With increasing water content, carbon-13 T ₁ relaxation time constants for PVP, measured under the same conditions as above, indicate a major increase in the molecular mobility of carbon atoms associated with the pyrrolidone side chains.     

Magnetic Resonance Microscopy for Assessment of Morphological Changes in Hydrating Hydroxypropylmethylcellulose Matrix Tablets In Situ–Is it Possible to Detect Phenomena Related to Drug Dissolution Within the Hydrated Matrices?

Purpose

So far, the hydrated part of the HPMC matrix has commonly been denoted as a “gel” or “pseudogel” layer. No MRI-based results have been published regarding observation of internal phenomena related to drug dissolution inside swelling polymeric matrices during hydration. The purpose of the study was to detect such phenomena.

Methods

Multiparametric, spatially and temporally resolved T₂ MR relaxometry, in situ, was applied to study formation of the hydration progress in HPMC matrix tablets loaded with L-dopa and ketoprofen using a 11.7 T MRI system. Two spin-echo based pulse sequences were used, one of them specifically designed to study short T₂ signals.

Results

Two components in the T₂ decay envelope were estimated and spatial distributions of their parameters, i.e. amplitudes and T₂ values, were obtained. Based on the data, different region formation patterns (i.e. multilayer structure) were registered depending on drug presence and solubility. Inside the matrix with incorporated sparingly soluble drug a specific layer formation due to drug dissolution was detected, whereas a matrix with very slightly soluble drug does not form distinct external “gel-like” layer.

Conclusions

We have introduced a new paradigm in the characterization of hydrating matrices using ¹H MRI methods. It reflects molecular mobility and concentration of water inside the hydrated matrix. For the first time, drug dissolution related phenomena, i.e. particular front and region formation, were observed by MRI methods.     

The Effect of Formulation Composition and Dissolution Parameters on the Gel Strength of Controlled Release Hydrogel Tablets

The impact of hydrogel polymers and dissolution media on tablet gel strength, Γ, of controlled release (CR) hydrogel tablets was investigated. CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo® lactose, to produce tablets with a polymer content of 8, 15, and 30% w/w. Γ was measured using a previously reported method. The drug dissolution profiles were similar, irrespective of polymer type or dissolution media (DI water, 0.1 N HCl, and pH 6.8 phosphate buffer), at the same % w/w level of polymer. Γ, however, showed large and significant differences (p≤0.05) between tablets containing different polymers and between different dissolution media. Γ values were HPMC K100MP > HPC HXF > carbomer 971P (same % w/w) with absolute Γ values at 30% w/w in DI water of 6600, 4600, and 1600 ergs/cm³, respectively. Γ for HPMC based tablets was independent of changes in dissolution media, while the Γ values for HPC tablets were 18% lower in acid and buffer than in DI water. Of the polymers tested, carbomer based tablets had the lowest Γ values in all dissolution media and an unexpected 58% lower Γ in buffer compared with DI water or acid. Γ provides a quantitative measure of the effect of formulation and dissolution parameter changes on tablet gel layer strength, under in vitro stress conditions that may parallel in vivo tablet performance, but which cannot be deduced from a comparison of dissolution profiles or polymer viscosity.     

Formulation and evaluation of mucoadhesive buccal films impregnated with carvedilol nanosuspension: a potential approach for delivery of drugs having high first-pass metabolism

Abstract

Context: Mucoadhesive buccal films containing three layers (mucoadhesive layer, nanosuspension containing layer and backing membrane) were incorporated with carvedilol nanosuspension.

Objective: Formulation and evaluation of nanosuspension incorporated mucoadhesive buccal films of carvedilol for bioavailability enhancement by avoiding first-pass metabolism.

Methods: Carvedilol-loaded nanosuspension was prepared by a precipitation–ultrasonication method with varying concentrations of the polymer. The formulation was analyzed for size, size distribution, surface charge and morphology. Optimized nanosuspension was incorporated into drug gel layer which was sandwiched between a mucoadhesive layer and a backing layer to form tri-layered buccal films. They were evaluated for their physical, mechanical and bioadhesive parameters followed by in vitro and in vivo studies.

Results and discussion: Nanosuspension showed a negative zeta potential (?17.21?mV) with a diameter of around 495 nm and a polydispersity index of 0.203. Nanosuspension incorporated drug gel layer (62.4% drug loading) was optimized to contain 3% HPMC and 50?mg Carbopol 934P. The mucoadhesive layer and the backing layer were optimized to contain 3% HPMC and 1% ethyl cellulose, respectively. In vitro drug release was 69% and 62.4% in 9?h across synthetic membrane and porcine buccal mucosa, respectively. In vivo studies conducted in rabbit model showed 916% increase in the relative bioavailability in comparison to marketed oral tablet formulation. The C_max and T_max of the prepared formulation increased due to increased surface area of drug and also by-passing hepatic metabolism.

Conclusion: The drug delivery system has been designed as a novel platform for potential buccal delivery of drugs having high first-pass metabolism.     

Formulation development and optimization of bilayer tablets of aceclofenac

Objective: The objective of the present study was to develop bilayer tablets of aceclofenac that are characterized by initial burst drug release followed by sustained release of drug.

Methods: The fast-release layer of the bilayer tablet was formulated using microcrystaline cellulose (MCC) and HPMC K4M. The amount of HPMC E4M (X₁) and MCC (X₂) was used as independent variables for optimization of sustained release formulation applying 3² factorial design. Three dependent variables were considered: percentage of aceclofenac release at 1 h, percentage of aceclofenac release at 12 h, and time to release 50% of drug (t_50%). The composition of optimum formulation of sustained release tablets were employed to formulate double layer tablets.

Results: The results indicate that X₁ and X₂ significantly affected the release properties of aceclofenac from sustained release formulation. The double layer tablets containing fast-release layer showed an initial burst drug release of more than 30% of its drug content during first 1 h followed by sustained release of the drug for a period of 24 h.

Conclusion: The double layer tablets for aceclofenac can be successfully employed as once-a-day oral-controlled release drug delivery system characterized by initial burst release of aceclofenac for providing the loading dose of drug.     

The Properties of HPMC:PEO Extended Release Hydrophilic Matrices and their Response to Ionic Environments

Purpose

Investigate the extended release behaviour of compacts containing mixtures of hydrophilic HPMC and PEO in hydrating media of differing ionic strengths.

Methods

The extended release behaviour of various HPMC:PEO compacts was investigated using dissolution testing, confocal microscopy and magnetic resonance imaging, with respect to polymer ratio and ionic strength of the hydrating media.

Results

Increasing HPMC content gave longer extended release times, but a greater sensitivity to high ionic dissolution environments. Increasing PEO content reduced this sensitivity. The addition of PEO to a predominantly HPMC matrix reduced release rate sensitivity to high ionic environments. Confocal microscopy of early gel layer development showed the two polymers appeared to contribute independently to gel layer structure whilst together forming a coherent and effective diffusion barrier. There was some evidence that poorly swollen HPMC particles added a tortuosity barrier to the gel layer in high ionic strength environments, resulting in prolonged extended release. MRI provides unique, non-invasive spatially resolved information from within the HPMC:PEO compacts that furthers our understanding of USP 1 and USP 4 dissolution data.

Conclusions

Confocal microscopy and MRI data show that combinations of HPMC and PEO have advantageous extended release properties, in comparison with matrices containing a single polymer.

     

Factors affecting drug release from hydroxypropyl methylcellulose matrix systems in the light of classical and percolation theories

Importance of the field: Hydroxypropyl methylcellulose (HPMC) is a versatile polymer widely used in the preparation of pharmaceutical dosage forms. The behavior of this polymer is a key factor in designing a variety of controlled release systems, especially hydrophilic matrices in which HPMC can be the only substance responsible for controlling the release rate of the drug.

Areas covered in this review: A new approach, proposed in 2004, based on percolation theory to explain the influence of the main formulation factors on drug release from HPMC matrices has been analyzed, paying attention to the advantages with respect to previous theories.

What the reader will gain: The influence of especially important factors such as polymer concentration and particle size is now much better known thanks to these new theories.

Take home message: To formulate a HPMC matrix, the system must be above the polymer's critical point, that is, allowing HPMC to act as outer phase. In this way, a coherent gel layer will be obtained because the first moment and the drug release will be controlled by this layer. Furthermore, knowing the critical points allows the vicinity of these points to be avoided, which are regions of high variability. In this way, robust dosage forms can be obtained.     

曲尼司特缓释片的制备及其释药影响因素研究

目的 制备了曲尼司特凝胶骨架片。方法 采用HPMC K4M、K15M为凝胶骨架材料，进行了处方研究；通过测定制剂体外释放度，评价了该缓释片处方。结果 曲尼司特缓释片体外释药符合Higuchi方程，其释药速率常数Kr为0．193h^1/2。影响缓释片体外释药的因素有骨架材料的种类、用量、粘合剂的种类和释药介质的pH等。结论 缓释片具有明显的缓释作用，可缓慢释药12h。     

Synchronized Release of Sulpiride and Sodium Decanoate from HPMC Matrices: A Rational Approach to Enhance Sulpiride Absorption in the Rat Intestine

Purpose. (a) To improve the absorption of sulpiride (SP) through the intestinal wall by incorporating it together with sodium decanoate (SD) into erodible matrices, designed to synchronize the release of SP and SD over different periods of time; (b) to test, in vivo the hypothesis that this simultaneous release increases SP absorption from the intestinal lumen. Methods. Matrix tablets, possessing different erosion rates, were prepared by changing the ratios between SD and hydroxypropyl methylcellulose (HPMC). The amounts of HPMC varied from 2.5% to 17% w/w. Double layer tablets, containing similar amounts of SP, SD, and HPMC were used as nonsynchronous controls. The erosion kinetics of the tablets was assessed gravimetrically in vitro in USP basket dissolution apparatus and in vivo in the intestine of the anesthetized rat after intra-intestinal administration. SP absorption was studied after intra-intestinal administration of the different kinds of tablets to anesthetized rats, by monitoring SP blood levels. SP and SD levels in the withdrawn samples from the dissolution systems and blood were analyzed by HPLC. Results. The controlled erosion of the tablets resulted in equal release rates of SP and SD during the initial linear phase of the process. This synchronized release lasted over different time periods depending on the relative amount of HPMC in the formulations (from 1 hour to 4 hours for 2.5 and 17 % w/w of HPMC, respectively). The synchronous matrices increased SP bioavailability after intra-intestinal administration. The increase varied from 1.4 to 2.3-fold for the slow and the fast release formulations, respectively (compared with the nonsynchronous, SD containing control formulations), indicating the ability to control both erosion rate and length of intestinal segment in which absorption is taking place. Conclusions. SP bioavailability after intestinal administration can be improved only if SP is released together with SD along the entire intestinal route. This can be accomplished by the design of synchronous matrices capable of concomitant release of SP and SD despite the differences in their water solubility. The ability to manipulate and control the duration of the synchronous phase of the matrices makes it possible for SP to be absorbed at different parts of the intestine.     

Initial studies of water granulation of eight grades of hypromellose (HPMC)

The purpose of this study is to investigate the water granulation mechanism of the hydrophilic matrix polymer HPMC in a high shear mixer and to relate the properties of the granules and tablets to the molecular weight and the degree of substitution for eight HPMC grades. Although the hydrophilic matrix system is a well known drug delivery one, there is a difficulty in that the desirable water granulation technique often causes problems in the presence of relatively large amounts of HPMC due to its hydrophilicity. The results of this study show that the properties of the granules and the tablets fall into two groups according to whether the molecular weight of the polymer is high or low. The granules of low molecular weight were smaller and more compact, with better flow properties but with less tensile strength of the compacts, whereas the opposite was valid for granules of high molecular weight. The explanation for these differences is linked to the proposed granulation mechanism of HPMC, in which the properties of the gel layer are important. The dominant factors governing the properties are the molecular weight and, to lesser extent, the degree of substitution.     

羟丙基甲基纤维素的凝胶特性及其对曲尼司特缓释片释放行为的影响

目的：研究羟丙基甲基纤维素(HPMC)的凝胶特性及其对曲尼司特缓释片释放行为的影响。方法：采用称重法、图像法和体积测量法,研究HPMC辅料片和曲尼司特缓释片在不同pH环境中的水合度和溶胀度。结果：辅料片在SGF和SIF中的水合速率常数分别为0.897 h-1和0.681 h-1;溶胀速率常数分别为1.005 h^-1和0.713 h^-1。曲尼司特缓释片在SGF中,在0.5 h内迅速水合和溶胀,其后呈负增长;而在SIF中,重量和体积都缓慢增加,5 h后重量稍有下降,体积保持不变。结论：HPMC水凝胶的形成速度和形态与介质的pH有关,凝胶层的溶蚀速度控制药物的释放。     

Characterization of 5-Fluorouracil Release from Hydroxypropylmethylcellulose Compression-Coated Tablets

Hydrogel compression-coated tablets are able to release the core drug after a period of lag time and have potential for colon-specific drug delivery based on gastrointestinal transit time concept. This study investigated the factors influencing in vitro release characteristics of a model drug 5-fluorouracil from hydroxypropylmethycellulose (HPMC) compression-coated tablets. The core tablet, prepared by a wet granulation compression method, was designed to disintegrate and dissolute quickly. To prepare the compression-coated tablets, 50% of the HPMC/lactose coat powder was precompressed first, followed by centering the core tablet and compressing with the other 50% of the coat powder. Release characteristics were evaluated in distilled water by using a Chinese Pharmacopoeia rotatable basket method. Effect of HPMC viscosity, lactose content in outer shell, and overall coating weight of outer shell on release lag time (T_lag), and zero-order release rate (k) were studied. Release of drug from compression-coated tablets began after a time delay as a result of hydrogel swelling/retarding effect, followed by zero-order release for most of the formulations studied. HPMC of higher viscosity (K4M and K15M) provided better protection of the drug-containing core, showing increased release lag time and slower release rate. Incorporating lactose in outer shell led to decrease of T_lag and increase of k. T_lag and k are exponentially and linearly correlated to lactose content, expressed as weight percentage of the outer shell. Larger coating weight (W) of outer shell produced larger coating thickness (D) around core tablet, which resulted in increase in T_lag and decrease in k. There was good fitting of a linear model for each of the four variables W, D, T_lag, and k. Hardness of the compression-coated tablets and pHs of the release media had little effect on drug release profile. It is concluded that the release lag time and release rate are able to be tailored through adjusting the formulation variables to achieve colon-specific drug delivery of 5-fluorouracil.     

Pharmacokinetics and analgesic effect of ketorolac floating delivery system

Abstract

Objectives: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form.

Methods: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay.

Results: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8?h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the C_max (2.2?±?0.3?µg/ml) was achieved at ～2?h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets.

Conclusion: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.     

Dependence of the Molecular Mobility and Protein Stability of Freeze-Dried γ-Globulin Formulations on the Molecular Weight of Dextran

Purpose. The effect of the molecular weight of dextran on the molecular mobility and protein stability of freeze-dried serum -globulin (BGG) formulations was studied. The stabilizing effect of higher molecular weight dextran is discussed in relation to the molecular mobility of the formulations. Methods. The molecular mobility of freeze-dried BGG formulations containing dextrans of various molecular weights was determined based on the free induction decay of dextran and water protons measured by proton NMR. The protein stability of the formulations was determined at temperatures ranging from 20 to 70°C by size exclusion chromatography. Results. Changes in the molecular mobility of freeze-dried formulations that occurred at temperatures below the glass transition temperature could be detected as the molecular mobility-changing temperature (T_mc), at which dextran protons started to exhibit a Lorentzian relaxation decay due to higher mobility in addition to a Gaussian relaxation decay. T_mc increased as the molecular weight of dextran increased. The proportion of dextran protons which exhibited the higher mobility relaxation process (P_hm) at temperatures above T_mc decreased as the molecular weight of dextran increased. Protein stability was closely related to molecular mobility. The temperature dependence of the denaturation rate changed at around T_mc, and denaturation in the microscopically liquidized state decreased as P_hm decreased with increasing molecular weight of dextran. Conclusions. The effect of the molecular weight of dextran on the protein stability of freeze-dried BGG formulations could be explained in terms of the parameters obtained by ¹H-NMR such as T_mc and P_hm. These parameters appear to be useful in preformulation and stability prediction of freeze-dried formulations.     

The effect of formulation composition and dissolution parameters on the gel strength of controlled release hydrogel tablets.

The impact of hydrogel polymers and dissolution media on tablet gel strength, Gamma, of controlled release (CR) hydrogel tablets was investigated. CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo lactose, to produce tablets with a polymer content of 8, 15, and 30% w/w. Gamma was measured using a previously reported method. The drug dissolution profiles were similar, irrespective of polymer type or dissolution media (DI water, 0.1 N HCl, and pH 6.8 phosphate buffer), at the same % w/w level of polymer. Gamma, however, showed large and significant differences (p < or = 0.05) between tablets containing different polymers and between different dissolution media. Gamma values were HPMC KI00MP > HPC HXF > carbomer 971P (same % w/w) with absolute Gamma values at 30% w/w in DI water of 6600, 4600, and 1600 ergs/cm3, respectively. Gamma for HPMC based tablets was independent of changes in dissolution media, while the Gamma values for HPC tablets were 18% lower in acid and buffer than in DI water. Of the polymers tested, carbomer based tablets had the lowest Gamma values in all dissolution media and an unexpected 58% lower Gamma in buffer compared with DI water or acid. Gamma provides a quantitative measure of the effect of formulation and dissolution parameter changes on tablet gel layer strength, under in vitro stress conditions that may parallel in vivo tablet performance, but which cannot be deduced from a comparison of dissolution profiles or polymer viscosity.