AGGREGATION DURING THE DISSOLUTION OF DIAZEPAM IN INTERACTIVE MIXTURES

The dissolution of micronized diazepam (1.0-10.0%) in interactive mixtures with lactose-povidone, Emdex®, TabBase® and Compactrol® as carriers was investigated using the USP paddle method and distilled water as the dissolution medium. Dissolution rate of the binary diazepam-carrier mixtures increased using more soluble carriers such as lactose-povidone and decreased as the diazepam concentration of the mixtures increased. The data were interpreted by considering dissolution from both dispersed and aggregated particles and modelled using monoexponential and biexponential equations allowing the estimation of reciprocal dissolution rate constants for dispersed and aggregated particles (k_d and k_a and initial aggregate concentrations (C_a). The estimated k_d parameters were independent of carrier and diazepam concentration while the ka. parameters varied and were dependent on the aggregate size distribution in the interactive mixtures studied. The degree of aggregation increased markedly with increasing diazepam concentration and was greatest for the less soluble carrier, Compactrol®. Ternary surfactant interactive mixtures containing diazepam and sodium lauryl sulphate (100:2) adhered to the carrier surface were developed and demonstrated improved dissolution rates which were attributed to the deaggregation effect of the surfactant in the aggregate microenvironment. The effect was most noticeable at 10 percent drug loadings where the surfactant concentration was greatest and where both the k_a and C_a parameters were minimized.     

Some Properties of Diazepam-Polyethylene Glycol 6000 Solid Dispersions and their Modification in the Presence of Stearic Acid of Polysorbate 80

Abstract

Physical mixtures and melts of diazepam and polyethylene glycol 6000 (PEG 6000) have been studied by Differential Scanning Calorimetry (DSC) and Differential Thermal Analysis (DTA). Problems were encountered in determining the precise position of the eutectic which contained <30% diazepam. Melts contained amorphous diazepam and, immediately after preparation, an unstable form of PEG 6000 which transformed on storage to a more stable form, probably folded crystals. Dissolution rates were determined by constant surface area methodology and were greatest in melts containing 15% diazepam. The inclusion of 1 or 5% polysorbate 80 or 1% stearic acid into the melts slightly increased the dissolution rates from dispersions containing 5, 10 or 15% diazepam but especially from dispersions containing 20% diazepam. A limited 4-week ageing study indicated that age-induced changes depended on both the storage temperature and diazepam concentration. The inclusion of either stearic acid or polysorbate 80 appeared not to protect dissolution rates against ageing     

Pharmacokinetics of Sulfisoxazole Solid Dispersions in Rabbis

Abstract

The approach of solid dispersion was found useful for optimizing the pharmacokinetics of sulfisoxazole in Rabbits. This was illustrated on the example of bicomponent solid dispersions containing water-soluble, urea and pvp 25000, and water insoluble, DCA and GMS, carriers. The effect of the type and concentration of the inert carrier was investigated and found to influence the pharmacokinetic parameters studied to different extents. The multicomponent (Tri and quaternary) solid dispersions implied different effects on the pharmacokinetics of sulfisoxazole according to the nature and the proportion of the carrier used. Dispersing sulfisoxazole in the solid state in innert carriers such as GMS, DCA, urea and PVP was shown to influence significantly the dissolution rate of the drug to different extents. Dispersion of sulfisoxazole in soluble carriers resulted in significant enhancement of the dissolution rate whatever the equipment used. Correlation of sulfisoxazole in-vitro dissolution rate parameters, D.E. and t_75%, to the pharmacokinetic parameters revealed no or very poor correlation.However, the t_75% parameter by the USP disintegration tester may be considered to exhibit the most reasonable correlation to the pharmacokinetic parameter K_e.     

Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion

ABSTRACT

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop®. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630®), and ethyl acrylate, methyl methacrylate polymer (Eudragit® EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T_gs were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N–H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit® EPO solid dispersion and Nimotop®, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC_{0–12 hr} values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

Dissolution from ordered mixtures: The effect of stirring rate and particle characteristics on the dissolution rate.

Different particle size fractions of three carriers were used to prepare ordered mixtures of frusemide. The dissolution of these mixtures were compared with a frusemide suspension and pure frusemide agglomerates by the USP XXI paddle method at three rotational speeds.

The dissolution of mixtures containing a highly soluble carrier (sodium chloride) were comparable to the suspension depending on the particle size of the carrier. Insoluble carriers (dicalciumphosphatedihydrate and microcrystalline cellulose) increased the dissolution, but the enhancement depended on the rotational speed, the particle size and the density of the carrier.     

Kozeny–Carman permeability relationship with disintegration process predicted from early dissolution profiles of immediate release tablets

This study was oriented toward the disintegration profiling of the diclofenac sodium (DS) immediate-release (IR) tablets and development of its relationship with medium permeability k_perm based on Kozeny–Carman equation. Batches (L1–L9) of DS IR tablets with different porosities and specific surface area were prepared at different compression forces and evaluated for porosity, in vitro dissolution and particle-size analysis of the disintegrated mass. The k_perm was calculated from porosities and specific surface area, and disintegration profiles were predicted from the dissolution profiles of IR tablets by stripping/residual method. The disintegration profiles were subjected to exponential regression to find out the respective disintegration equations and rate constants k_d. Batches L1 and L2 showed the fastest disintegration rates as evident from their bi-exponential equations while the rest of the batches L3–L9 exhibited the first order or mono-exponential disintegration kinetics. The 95% confidence interval (CI_95%) revealed significant differences between k_d values of different batches except L4 and L6. Similar results were also spotted for dissolution profiles of IR tablets by similarity (f₂) test. The final relationship between k_d and k_perm was found to be hyperbolic, signifying the initial effect of k_perm on the disintegration rate. The results showed that disintegration profiling is possible because a relationship exists between k_d and k_perm. The later being relatable with porosity and specific surface area can be determined by nondestructive tests.     

Dissolution Rate A Measurement of the Deaggregation of Furosemide Agglomerates During An Interactive Mixing Process

Abstract

Agglomerates of drug particles must be broken down and single particles attached to the carrier to ensure a completely random interactive mixture. Here it was found that the dissolution rates of samples from interactive mixtures compared to suspended furosemide was an indication of the deaggregation of furosemide agglomerates during an interactive mixing process. Deaggregation depended on the forces generated during mixing and was quicker when a high density carrier such as sodium chloride was used.     

Influence of selected water soluble carbohydrates on the dissolution profile of prednisolone

Abstract

The utilization of three water soluble carbohydrates as carrier to improve the dissolution rate of prednisolone was studied. Coprecipitates and physical mixtures of the drug and the carriers in three different proportions were prepared and their dissolution profile was compared with the dissolution profile of the pure drug. The remarkably fast and erratic dissolution of prenisolone observed from the coprecipitates was possible due to the conversion of prednisolone into its metastable or amorphous form durning the coprecipitation process. The dissolution rate of the drug from the physical mixtures was much higher than from the pure drug itself. Effect of aging of the coprecipitate on the dissolution profile showed an increasing tendency of the dissolution curve to match with that of the corresponding physical mixture.     

Bioequivalence Evaluation of Two Formulations of Doxazosin Tablet in Healthy Thai Male Volunteers

ABSTRACT

The bioequivalence of two doxazosin 2 mg tablets was determined in 24 healthy Thai male volunteers after one single dose in a randomized cross-over study with a one week washout period. The study was conducted at Faculty of Pharmaceutical Sciences and Health Sciences Research Institute, Naresuan University, Phitsanulok, Thailand. Reference (Cardura®, Heinrich Mack Nachf. GmbH & Co. GK, Illertissen, Germany) and test (Dozozin-2®, Umeda Co., Ltd., Bangkok Thailand) were administered to volunteers after overnight fasting. Blood samples were collected at specified time intervals and plasma was separated. The validated HPLC method with fluorescence detection was used for quantification of doxazosin in plasma samples. The pharmacokinetic parameters, T_max, C_max, AUC_t, AUC_∞, T_1/2, λ_z, Cl and V_d, were determined from plasma concentration time profile of both formulations by using non-compartment analysis. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands. The analysis of variance (ANOVA) using log-transformed C_max, AUC_t, and AUC_∞ did not show any significant difference between two formulations. The point estimates and 90% confidence intervals for C_max, AUC_t and AUC_∞ were within the acceptance range (0.80–1.25), satisfying the bioequivalence criteria of the Thailand Food and Drug Administration Guidelines. These results indicate that Dozozin-2® is bioequivalent to Cardura® and, thus, may be prescribed interchangeably.     

Characterization and Dissolution Study of Oxodipine from Solid Binary Systems

Thennomicroscopy and differential scanning calorimetry were employed to characterize solid binary systems prepared with oxodipine and PEG 6000, 2-hydroxypropyl-β-cyclodextrin or mannitol. DSC curves did not allow to diferentiate physical mixtures from solid dispersions. Thennomicroscopy revealed the interactions that can be produced between drug and each carrier, due to heat contribution, when the physical mixtures were observed; also this thermal technique permited us to ascertain the composition of particles that constitute the solid dispersions. Dissolution studies showed that the amelioration obtained in oxodipine dissolution from physical mixtures was due to the dessagregant action of the carriers, which obtained an increase of the drug surface in contact with the dissolution medium. The proportions and carrier nature influence the oxodipine dissolution, fundamentally from solid dispersions, where the interaction drug/carrier is stronger than in physical mixtures.     

Characterization of the Absorption of Theophylline From Immediate- and Controlled-Release Dosage Forms With a Numerical Approach Using the In Vitro Dissolution-Permeation Process Using Caco-2 Cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10^{? 6}–5.28 10^{? 6} cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (F_a) against experimental dissolved fractions (F_d) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed F_a/F_d relationships and theoretical F_a/F_d relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.     

Comparative Bioavailability Study of Two Controlled-Release Pentoxifylline Tablet Preparations

The bioavailability of a generic preparation of pentoxifylline sustained-release (SR) tablet was evaluated in comparison with a proprietary product (Trental 400®). For the study, 12 healthy male volunteers participated; the study was conducted according to a randomized, two-way crossover design. The bioavailability was compared using the parameters total area under the plasma level-time curve AUC_0?∞, peak plasma concentration C_max, and time to reach peak plasma concentration T_max. No statistically significant difference was observed between the values of the two products in all three parameters. The 90% confidence interval for the ratio of the logarithmic transformed AUC_0?∞ values of the generic pentoxifylline over those of Trental 400 was found to lie between 0.83 and 1.00, while that of the parameter C_max was between 0.91 and 1.29. In addition, elimination half-life t_1/2 and apparent volume of distribution V_d were calculated. There was no statistically significant difference between the t_1/2V_d values obtained from the data of the two preparations.     

Drug Release from Spray Layered and Coated Drug-Containing Beads: Effects of pH and Comparison of Different Dissolution Methods

Based on dissolution profiles of three model drugs on spray layered beads with the same percentage of Aquacoat® coating, it was concluded that in vitro dissolution of oral controlled–release formulations should be performed in both gastric and intestinal media for ionizable drugs. Ketoprofen (weak acid, pK_a 4.8), nicardipine HCl (salt of weak organic base, pK_a8.6), and acetaminophen (very weak organic acid, pK_a9.7, not ionized at physiologic pH) provided different dissolution characteristics in enzyme–free simulated gastric fluid (pH 1.4) and enzyme–free simulated intestinal fluid (pH 7.4), indicating that the rate of drug release was pH dependent and related to drug ionization even though the solubility of the coating (ethylcellulose) is pH independent. In acidic media, ketoprofen release from the beads containing low–level coating (3%) was slower than that of nicardipine HCl, with the opposite holding true in basic media. Acetaminophen was released at approximately the same rate in both acidic and basic media. A comparison of drug release profiles for nicardipine HCl nude beads was also investigated among three different dissolution methods: USP dissolution apparatus I (basket method, 50 rpm), USP dissolution apparatus II (paddle method, 50 rpm), and USP dissolution apparatus III (Bio–Dis®, Van–Kel Industries, 5 and 10 dpm). Release profiles obtained from all methods were similar, indicating that the three dissolution methods were comparable.     

Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben^® product.     

Artificial Neural Networks: Comparison of Two Programs for Modeling a Process of Nanoparticle Preparation

ABSTRACT

Artificial Neural Networks (ANNs) were used to predict nanoparticle size and micropore surface area of polylactic acid nanoparticles, prepared by a double emulsion method. Different batches were prepared while varying polymer and surfactant concentration, as well as homogenization pressure. Two commercial ANNs programs were evaluated: Neuroshell® Predictor, a black-box software adopting both neural and genetic strategies, and Neurosolutions®, allowing a step-by-step building of the network. Results were compared to those obtained by statistical method. Predictions from ANNs were more accurate than those calculated using non-linear regression. Neuroshell® Predictor allowed quantification of the relative importance of the inputs. Furthermore, by varying the network topology and parameters using Neurosolutions®, it was possible to obtain output values which were closer to experimental values. Therefore, ANNs represent a promising tool for the analysis of processes involving preparation of polymeric carriers and for prediction of their physical properties.     

Formulation and pharmacokinetics of gelucire solid dispersions of flurbiprofen

Context: Development of solid dispersions is to improve the therapeutic efficacy by increasing the drug solubility, dissolution rate, bioavailability as well as to attain rapid onset of action.

Objective: The present research deals with the development of solid dispersions of flurbiprofen which is poorly water soluble to improve the solubility and dissolution rate using gelucires.

Materials and methods: In this study, solid dispersions were prepared following solvent evaporation method using gelucire 44/14 and gelucire 50/13 as carriers in different ratios. Then the formulations were evaluated for different physical parameters, solubility studies, DSC, FTIR studies and in vitro dissolution studies to select the best formulation that shows rapid dissolution rate and finally subjected to pharmacokinetic studies.

Results and discussion: From the in vitro dissolution study, formulation F3 showed the better improvement in solubility and dissolution rate. From the pharmacokinetic evaluation, the control tablets produced peak plasma concentration (C_max) of 9140.84?±?614.36?ng/ml at 3?h T_max and solid dispersion tablets showed C_max?=?11?445.46?±?149.23?ng/ml at 2?h T_max. The area under the curve for the control and solid dispersion tablets was 31?495.16?±?619.92 and 43?126.52?±?688.89?ng h/ml and the mean resident time was 3.99 and 3.68?h, respectively.

Conclusion: From the above results, it is concluded that the formulation of gelucire 44/14 solid dispersions is able to improve the solubility, dissolution rate as well as the absorption rate of flurbiprofen than pure form of drug.     

Dielectric relaxation and thermal studies on dispersed phase polymer nanocomposite films

Dispersed phase polymer nanocomposite films (PNC) based on PMMA–LiClO₄+ n-YSZ, has been prepared. The effect of filler concentration on dielectric constant, tanδ and ac conductivity has been observed. For each PNC films the activation energy for relaxation (E_τ) is almost same as the activation energy for ion conduction (E_a). The dc conductivity, the hopping frequency of charge carriers have been obtained at different temperature from the analysis of the ac conductivity data. For all the PNC films, the concentration of charge carriers has been calculated at different temperature using Almond–West formalism. The estimated activation energies for the dc conductivity and the hopping frequency are different, which indicates that the both charge carrier mobility and concentration contribute significantly to the ionic conductivity of polymeric electrolyte. Contribution of charge carrier mobility to the total conductivity has also been confirmed from the differential scanning calorimetry analysis. Improvement in thermal stability has been noticed with filler addition.     

Development of isradipine loaded self-nano emulsifying powders for improved oral delivery: in vitro and in vivo evaluation

Isradipine (ISR) is a potent calcium channel blocker with low oral bioavailability due to low aqueous solubility, extensive first-pass metabolism and P-glycoprotein (P-gp)-mediated efflux transport. In the present investigation, an attempt was made to develop isradipine-loaded self-nano emulsifying powders (SNEP) for improved oral delivery. The liquid self-nano emulsifying formulations (L-SNEF/SNEF) of isradipine were developed using vehicles with highest drug solubility, i.e. Labrafil® M 2125 CS as oil phase, Capmul® MCM L8 and Cremophor® EL as surfactant/co-surfactant mixture. The developed formulations revealed desirable characteristics of self-emulsifying system such as nano-size globules ranging from 32.7 to 40.2?nm, rapid emulsification (around 60?s), thermodynamic stability and robustness to dilution. The optimized stable self-nano emulsifying formulation (SNEF₂) was transformed into SNEP using Neusilin US2 (SNEP_N) as adsorbent inert carrier, which exhibited similar characteristics of liquid SNEF. The solid state characterization of SNEP_N by Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopic studies shown transformation of crystalline drug into amorphous form or molecular state without any chemical interaction. The in vitro dissolution of SNEP_N compared to pure drug was indicated by 18-fold increased drug release within 5?min. In vivo pharmacokinetic studies in Wistar rats showed significant improvement of oral bioavailability of isradipine from SNEP_N with 3- and 2.5-fold increments in peak drug concentration (C_max), area under curve (AUC_0–∞) compared to pure isradipine. In conclusion, these results signify the improved oral delivery of isradipine from developed SNEP.     

Solid State and Dissolution Rate Characterization of Co-Ground Mixtures of Nifedipine and Hydrophilic Carriers

ABSTRACT

Co-ground powders of the poorly water-soluble drug nifedipine and a hydrophilic carrier, [partially hydrolyzed gelatin (PHG), polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), urea or Pluronic F108] were prepared in order to improve the dissolution rate of nifedipine. The effects of type of grinding equipment, grinding time, and type of hydrophilic carrier on the crystallinity of nifedipine (x-ray diffraction and differential scanning calorimetry) on the interaction between drug and carriers (differential scanning calorimetry), on the particle size and appearance (scanning electron microscopy), on the wettability (contact angle measurements), and on the drug release were investigated. Grinding nifedipine together with these carriers improved the dissolution rate. PHG-ground mixtures resulted in the fastest dissolution rate followed by PVP, SDS, HPMC, Pluronic, urea, and PEG. This effect was not only due to particle size reduction, which increased in the order PHG < PEG = SDS < Pluronic < drug < urea < HPMC < PVP, but also resulted from the ability of some carriers (PVP and HPMC) to prevent reaggregation of the finely divided drug particles. PVP, HPMC, and PHG formed a powder with amorphous drug. The carriers improved the wettability of the ground products in the order HPMC < drug < urea < PVP < SDS < PHG < PEG < Pluronic. Differential scanning calorimetry (DSC) measurements gave valuable information about the nature of drug crystallinity and the interactions with the carriers within the ground mixtures.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.