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.     

不同载体对缬沙坦纳米骨架载药系统溶出行为和生物利用度影响的研究

目的 通过调节纳米骨架载药系统（NDDS）中载体类型和比例实现对缬沙坦体外溶出和体内生物利用度的调控。方法 以缬沙坦作为模型药物,分别选取酸性敏感材料Eudragit E100（E100）、碱性敏感材料Eudragit L100-55（L100-55）作为载体材料,介孔二氧化硅Sylysia 350（S350）、Aerosil 200（A200）作为纳米骨架,通过调节载体和骨架材料的类型和比例筛选出具有pH 1.2、6.8敏感释放行为的纳米骨架载体处方,考察缬沙坦在pH 1.2、6.8环境中释放和在大鼠体内的药动学行为特征。结果 筛选的pH 1.2敏感释放缬沙坦NDDS处方缬沙坦、S350、E100比例为1∶3∶1,pH 6.8敏感释放缬沙坦NDDS处方为缬沙坦、A200、L100-55比例为1∶1∶3。pH 6.8敏感释放处方可调控缬沙坦在肠道pH 6.8条件下特异性溶出;pH 1.2敏感释放处方在保持缬沙坦在pH 6.8高溶出特性的同时可特异性地提高胃部酸性条件下的药物释放。pH 1.2、6.8敏感释放缬沙坦NDDS均一定程度上改善了缬沙坦的生物利用度,其中pH 6.8敏感释放缬沙坦NDDS提高生物利用度的幅度更高,血药浓度变化比较平缓。结论 NDDS可以调控缬沙坦的体外溶出和生物利用度,有望应用于pH值敏感性难溶药物的递送。     

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.     

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.     

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 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.     

不同氢溴酸右美沙芬口服固体制剂的溶出度考察

目的：对6个厂家不同氢溴酸右美沙芬口服固体制剂进行体外溶出度考察，比较体外溶出情况，为临床用药提供参考。方法：采用转篮法，转速100 r·min^-1，用高效液相色谱法测定氢溴酸右美沙芬口服固体制剂在0.1 mol·L^-1盐酸溶液中的溶出曲线；以威布尔方程拟合溶出参数T₅₀、T_d、m，并对参数进行方差分析。结果：氢溴酸右美沙普通片、分散片、胶囊以及软胶囊的平均累积溶出度分别为94.3%、101.3%、105.2%、93.4%。溶出参数T₅₀、T_d差异较大，其中T₅₀最大的是最小的13.4倍。结论：氢溴酸右美沙片、分散片、胶囊以及软胶囊体外溶出行为差别大，产品质量存在较大差异。     

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.     

离子色谱法测定木糖醇中氯离子、硫酸根离子和磷酸根离子及不同级别产品质量状况的评价

目的建立离子色谱法同时测定木糖醇中氯离子、硫酸根离子和磷酸根离子的含量,并评价不同级别木糖醇中氯离子、硫酸根离子和磷酸根离子含量的质量状况。方法采用Dionex IonPac AS19阴离子分析柱(4 mm×250 mm,5μm),以氢氧化钾为淋洗液梯度洗脱,流速为1.0 mL·min~(-1),标准曲线法测定。样品用超纯水溶解并稀释后直接进样。结果氯离子、硫酸根离子和磷酸根离子分别在0.01~2.0μg·mL~(-1)、0.02~6.0μg·mL~(-1)、0.05~4.0μg·m L~(-1)内线性关系良好,r分别为0.9998、0.9995和0.9995;加样回收率(n=6)分别为96.4%、93.8%、99.3%,RSD分别为1.6%、3.2%、1.4%。结论本方法操作简便、灵敏、高效,可用于同时测定木糖醇中氯离子、硫酸根离子和磷酸根离子的含量,为其质量控制提供保证。     

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.