Solution-mediated phase transformation of salts during dissolution: investigation using haloperidol as a model drug

Soluble salts can undergo solution-mediated phase transformation to a lower solubility form due to pH gradients in the gastrointestinal tract. Therefore, dissolution rate rather than solubility may be the best predictor of bioavailability for such compounds. The purpose of this project was to examine the kinetics of the conversion of a basic compound, haloperidol, and its salt forms using a flow-through dissolution apparatus and rotating disk method in neutral conditions. The effects of buffer concentration, salt form, dissolution apparatus, and hydrodynamics were examined. Raman microscopy was used to characterize solids after dissolution. Haloperidol mesylate and haloperidol chloride showed a decrease in dissolution rate with time in the dissolution media. Haloperidol mesylate and haloperidol chloride dissolution rates also decreased with increasing buffer capacity. Raman microscopy confirmed phase conversion from the salt forms to the free base form in phosphate buffer. Hydrodynamics did not affect the time course of the solution-mediated phase transformation of salt forms. Dissolution and precipitation appear to be a function of pH close to the surface of the dissolving solid. In situations where equilibrium solubility of salts cannot be assessed experimentally, dissolution experiments are useful for examining the extent and duration of the dissolution rate enhancement.     

Effect of processing and formulation variables on the stability of a salt of a weakly basic drug candidate

The effect of some processing and formulation variables on the stability of tablets containing a crystalline salt of a triazine derivative was studied. The salt has a relatively low melting point and a low microenvironmental pH due to the weakly basic nature of the parent compound (pKa = 4.0). This compound decomposes through acid-catalyzed hydrolysis. A full factorial design was used to study the effect of three variables on tablet stability: aqueous wet granulation, ball milling of the salt and filler prior to manufacturing, and the inclusion of sodium carbonate in the formulation as a pH modifier. In addition to the factorial design experiments, a batch of tablets was prepared by wet granulation, using sodium bicarbonate as the pH modifier. Stability of the drug in tablets was evaluated at 40 degrees C/75% relative humidity (RH) and at 40 degrees C/ambient humidity. Stability of tablets was adversely affected by wet granulation. However, stability was greatly improved by wet granulation in the presence of sodium carbonate. While sodium carbonate enhanced drug stability in the tablets, regardless of the manufacturing process, wet granulated tablets were more stable than tablets containing sodium carbonate and prepared without wet granulation. Similarly prepared tablets by using sodium bicarbonate were remarkably less stable compared with those containing sodium carbonate. The use of sodium bicarbonate as a pH modifier resulted in only marginal enhancement of tablet stability, suggesting that a higher microenvironmental pH than that provided by sodium bicarbonate is needed to maximize stability. Despite the low lattice energy of the salt and the potential for disruption of salt crystallinity by mechanical stress, milling did not appear to have an adverse effect on tablet stability under the current experimental conditions. This study shows that selection of the proper manufacturing process, in conjunction with the appropriate pH modifier, could be critical to dosage form stability.     

不同载药方法对介孔二氧化钛纳米粒载药及药物溶出速率的影响

目的考察不同载药方法对介孔二氧化钛纳米粒载药系统载药和溶出速率的影响。方法通过溶剂挥干法、熔融法、吸附平衡法分别将卡维地洛包载于介孔二氧化钛纳米粒中,用扫描电镜和透射电镜观测样品形貌,氮气吸附-解吸法测量载体的比表面积和孔体积,差示扫描量热法分析药物粒子的存在状态,X-射线衍射法进行物相分析,热失重法分析载药量,最后测定载药系统的溶出速率并进行长期稳定性试验。结果三种载药方法均能通过改变药物的存在状态使药物以非晶型存在于载体中而达到提高溶出速率的目的。其中溶剂挥干法所得的载药系统溶出速率提高显著,并且更具有长期稳定性。结论溶剂挥干法为介孔二氧化钛纳米粒载药的首选。     

Effect of a basic organic excipient on the dissolution of diclofenac salts

Dissolution of diclofenac from compressed discs containing mixtures of a diclofenac salt and a basic excipient, in various w/w ratios, was examined. Two diclofenac salts, diclofenac deanol (DDNL) and diclofenac tert-butylamine, and the basic excipient 2-amino-2-methyl-1,3-propanediol (AMPD) were examined. Inclusion of the soluble basic excipient at high loadings enhanced the dissolution rate of diclofenac tert-butylamine fivefold; however, it retarded dissolution of the DDNL salt 40-fold in the weight fraction range 40-80% AMPD, despite the fact that AMPD is more than four times more soluble than DDNL. These findings were attributed to the solubilities of salts formed between diclofenac and the basic excipient used. The "salt conversion model" was developed to predict dissolution from mixtures of a salt of an ionizable drug and an ionizable excipient capable of forming a salt with the drug. Deviations from the model at high weight fractions of base and, in the case of the systems containing the more soluble drug, at low weight fractions of base were attributed to carrier-controlled dissolution. The present work illustrates that the solubility of potential salts, which may form between the drug and ionizable excipients present has an important influence on the dissolution of the drug from such compressed mixtures.     

Effect of pepsin on maintaining the supersaturation of the HCl salt of a weakly basic drug: a case study

The impact of pepsin on the maintenance of supersaturated solution of the HCl salt of a weakly basic drug was evaluated in simulated gastric fluid by monitoring the drug solubility in the absence and presence of pepsin. In the presence of pepsin, the HCl salt maintained its apparent solubility through 24?h, whereas, no such solubility advantage was seen in the absence of pepsin. Consequently, a minimum inhibitory concentration of pepsin is required for maintenance of supersaturation. In addition, NMR study seems to indicate a molecular level interaction between pepsin and HCl salt leading to a weak binding between the two. Therefore, for the HCl salts of weak bases having disproportionation potential, it is preferred that preformulation solubility studies are conducted in the presence of pepsin to reflect their in vivo behavior in maintaining supersaturation solubility.     

Evaluation of a convective diffusion drug dissolution rate model.

A recently introduced drug dissolution rate model based on convective diffusion was evaluated by experimentally determining dissolution rates. Alkyl p-aminobenzoates were used as the test compounds in a dissolution cell which promoted laminar flow of the liquid past the dissolving surface. The parameters evaluated were diffusivity, solubility, rate of shear, dissolving surface shape, and orientation of the surface relative to flow. The agreement between theory and experiment was quite satisfactory with respect to the functional dependence of the rate on these parameters as well as the actual magnitude of the rates.     

Measurement of dissolution rates of potassium chloride from various slow release potassium chloride tablets using a specific ion electrode

The in vitro rates of release of potassium ions from slow-release potassium chloride tablets from 12 sources have been compared. Dissolution rates were determined using a modified non-sink method and a modified sink method. Medicament release in both methods was continuously monitored using a potassium ion specific electrode. The release rate constants were derived and the applicability of the Noyes-Whitney equation, Hixson and Crowell's cube root law and Higuchi's equation was studied.     

Effect of polymers on dissolution from drug suspensions.

The effect of three viscosity grades of methylcellulose on the dissolution-dialysis rate of nitrofurantoin suspensions was investigated using a cell designed to provide a large surface area for dialysis. Apparent dialytic rate constants of drug dispersions and solutions were measured in 0.1 N HC1 and in pH 7.4 buffer. Samples containing methylcellulose had lower rates of dialysis, with the lowest rate being observed for samples in which the polymer was used as the suspending agent. The reduced rate of dialysis of the drug suspension containing methylcellulose is thought to be due to complexation of the drug in solution with the polymer as well as formation of microscopic regions of high viscosity surrounding the undissolved drug particles leading to a reduction in the dissolution rate of the drug. An empirical relationship was obtained to enable the estimation of the effective drug concentration in the dissolution chamber for drug dispersions. The method is based on utilizing dialysis rate data of drug solutions. This relationship could be used for comparing suspension formulations in terms of the amount of drug available for dialysis.     

Effect of particle dissolution rate on ocular drug bioavailability

Aqueous ophthalmic drug solutions typically exhibit low bioavailability due to various loss processes such as drainage, tear turnover, nonproductive absorption, and protein binding. Suspensions may improve bioavailability, but because of a short residence time and a low corneal permeability rate constant, the dissolution rate of the drug and its intrinsic solubility must be considered. The relationship between the various parameters affecting the relative dissolution rate have not heretofore been examined with respect to the eye. In the present study, a kinetic model that predicts ocular tissue drug levels for suspensions has been developed and tested using a steroid, fluorometholone, as the test drug suspension. The proposed model is able to predict the effects of particle size, concentration, and changes in drainage rate such that a reasonable a priori prediction of drug levels can be made.     

The physical characteristics of lyophilized tablets containing a model drug in different chemical forms and concentrations

Orodispersible tablets, usually prepared using freeze-drying method, are becoming a popular drug formulation for patients who have difficulties swallowing solid dosage forms. The influence of drug solubility and concentration on the physical characteristics of lyophilized tablets composed of mannitol and gelatin was investigated. Phenobarbital and phenobarbital sodium were studied as model drugs. The tablets were analyzed for mechanical strength using a new method employing Instron, a material testing apparatus. For tablets containing phenobarbital in the form of sodium salt, better mechanical strength was demonstrated than for tablets prepared with water insoluble phenobarbital--acid form. Besides, the mechanical characteristics of the tablets indicate that plasticity and porosity were reduced when sodium phenobarbital was incorporated at a higher dose. Lyophilized tablets were not hygroscopic and only a small increase of tablet mass by 1% and 3% was observed after 4 weeks of storage at 40% and 60% RH, respectively. All formulations disintegrated in seconds in water, at a temperature of 37 degrees C.     

The improvement of aqueous chemical stability of a model basic drug by ion pairing with acid groups of polyelectrolytes

Carbomer (C) and procaine (P) were selected respectively as models of polyelectrolyte (PE) and basic drug (B) of low stability in aqueous solution. The purpose of this investigation was to test if a (C-P) aqueous system provides a microenvironment in which P is less exposed to hydroxyl ion catalyzed degradation, its main degradation pathway over a wide pH range. It was determined that in (C-P) a high fraction of P was present in the form of ion pairs [RCOO-PH+] with the carboxylate groups of C. The [RCOO-PH+] fraction was above 97% for compositions containing higher than 50 mol% of P. The chemical stability of C-P was assayed at two selected pHs (7.5 and 8.5) in comparison with conventional reference solutions (RS) without C. Procaine in (C-P) was 4.2 and 6.2 times more stable than in its respective RS at the two conditions assayed. The stabilizing factor was calculated as the ratio of the rate constants k(obs)(RS)/k(obs)(C-P).Since C-B systems exhibit negative electrokinetic potential that attracts positive ions such as (H+) and repels negative ones such as (OH(-)), the stabilizing effect would be associated with the higher acidity of (C-P) environment, in which PH+ molecules attached to the PE should also have lower kinetic energy than those in the bulk medium.     

Common ion effect on solubility and dissolution rate of the sodium salt of an organic acid

The solubility and the dissolution rate of the sodium salt of an acidic drug (REV 3164; 7-chloro-5-propyl-1H,4H-[1,2,4]triazolo[4,3-alpha]quinoxaline-1,4-dione) decreased by the effect of common ion present in aqueous media. The solubility of the sodium salt of REV 3164 in a buffered medium was much lower than that in an unbuffered medium. Also, the presence of NaCl decreased its solubility in water. The apparent solubility product (K'sp) of the salt, however, did not remain constant when the concentration of NaCl was changed. A decrease in K'sp value with the increase in NaCl concentration was observed; for example, the K'sp values at 0 and 1 M NaCl were 7.84 X 10(-4) and 3.94 X 10(-4) M2, respectively. Even when corrected for the effect of ionic strength, the solubility product decreased. This decrease in the solubility product in the presence of NaCl indicated a decrease in the degree of self-association (increase in activity coefficient) of the drug in aqueous media.     

Effect of disintegrants on drug dissolution from capsules filled on a dosator-type automatic capsule-filling machine

Various levels of newer disintegrants were compared against 10% starch and 0% disintegrant in dicalcium phosphate-based hard gelatin capsules filled on an instrumented Zanasi machine at a constant compression force. Hydrochlorothiazide or acetaminophen were included for drug dissolution studies. Disintegration time, ejection force and overall running characteristics were also considered. In general, the modified celluloses were most effective in enhancing drug dissolution, followed, in order, by the modified starches, corn starch, cross-linked PVP and the control (0% disintegrant). Reducing the lubricant level (magnesium stearate) or using a more soluble drug (acetaminophen) required less modified cellulose (AcDiSol) to exert a similar effect on drug dissolution. Disintegration and dissolution data correlated best with the more soluble drug.     

氟哌啶醇季铵盐衍生物对大鼠心室肌细胞L型钙电流的影响

目的　研究氟哌啶醇季铵盐衍生物 (F2 )对大鼠心室肌细胞L型钙电流 (ICa)的影响。方法　采用酶急性分离的单个大鼠心室肌细胞 ,应用膜片钳全细胞记录技术 ,观察F2对ICa的影响。结果　F2 (1μmol·L-1)能抑制任何一膜电压下的ICa,使峰电流从 (1775 2± 36 0 4 ) pA减少至 (46 4±12 9 1) pA (n =8,P <0 0 1) ,并使ICa的电流 -电压曲线上移 ,但不改变ICa的电压依赖特征。结论　F2 对心肌细胞膜L型钙通道具有阻断作用     

Using biorelevant dissolution to obtain IVIVC of solid dosage forms containing a poorly-soluble model compound

The usefulness of selected biorelevant dissolution media (BDM) to predict in vivo drug absorption was studied. Dissolution profiles of solid formulations of a poorly soluble model compound were compared in BDM simulating fasted and two levels of fed state. A non-physiologically relevant medium containing the cationic surfactant, cetrimide, was also investigated. All the media studied were capable of differentiating between the formulations employed, with formulation A consistently ranking high and formulations C and D ranking low. An in vivo dog study was carried out and an attempt was made to obtain a level A correlation between the plasma absorption curves and in vitro dissolution curves, using non-linear regression software. The in vitro-in vivo correlation (IVIVC) models developed indicated that fed state media (BDM 3) containing high levels of both bile salts (BS) and lipolysis products (LP) were best able to predict in vivo pharmacokinetic parameters (Cmax and AUC) with prediction errors lower than 10%. Overall, design and use of appropriate media for in vitro dissolution is extremely important. This study demonstrates the potential of physiologically relevant media containing both BS and LP for use in formulation and early drug development.     

Theoretical dissolution model of poly-disperse drug particles in biorelevant media

The purpose of the present study was to construct the theoretical dissolution model of poly-disperse drug particles in biorelevant media containing bile salt/ lecithin aggregates (micelles or vesicles). The effective diffusion coefficient in the biorelevant medium and the particle size distribution of drug particles were simultaneously factored into the Nernst-Brunner equation. The effective diffusion coefficient of a drug in the biorelevant medium was calculated to be smaller than that in the blank buffer, since the diffusion coefficient of a drug bound to the aggregates became similar to that of the aggregates. The particle size distribution of a drug powder was simulated as the sum of mono-disperse fractions covering the particle size range. To verify the modified equation, the dissolution profile of griseofulvin and danazol in a taurocholic acid/egg lecithin (4:1 mixture, taurocholic acid = 0-30 mM) system was investigated. It was clearly demonstrated that both modifications on the Nernst-Brunner equation improved the prediction accuracy. When the effect of the particle size distribution was neglected, the theoretical curve underestimated the observed value at the early phase of dissolution process. When the diffusion coefficient of a free drug was used instead of the effective diffusion coefficient, the theoretical curve overestimated the observed value. The results of the present study suggested that the effect of the particle size distribution and the effective diffusion coefficient should be taken into consideration.     

Effect of solvent flow Reynolds number on dissolution rate of a nondisintegrating solid (potassium chloride).

An apparatus for measuring dissolution rates of solids in the form of disks was designed to possess the following features. The solvent flowed continuously and reproducibly past the disk at various rates associated with calculable Reynolds numbers, Re. The effluent solution was adequately mixed before analysis. The concentration of dissolved solute was much less than the solubility. The surface area of the disk in contact with the solvent was constant during measurements. The dissolution rate of the disk was reproducible, and the disk and its surface could be readily characterized. The apparatus was tested at 37 degrees with compressed potassium chloride and water. The intrinsic dissolution rate, G, was a linear function of Re from Re=360 to greater than 6000. This relationship enabled one unknown constant in each dissolution theory to be expressed in terms of Re. For the diffusion layer model, the thickness of this layer, calculated from the experimental value of G, agreed well with that calculated from the various physical properties, provided that natural convection did not predominate. The dissolution of potassium chloride in this system was, therefore, controlled by diffusion.