Solubility of solid solutes in HFA-134a with a correlation to physico-chemical properties

The reformulation of pressurized metered dose inhalers with HFAs from CFCs has given rise to many solubility challenges. Compounds and excipients previously used in CFCs were observed to have significantly different solubility values in HFA-134a. In this investigation, the solubility values of 36 solid organic solutes in HFA-134a were determined. The set of compounds display diverse physico-chemical properties and yielded solubility values that ranged over 4 orders of magnitude. The experimental solubilities were compared to calculated values obtained from ideal solubility theory as well as from regular solution theory. While the theoretical models did not offer absolute solubility estimations, a clear correlation with the ideal solubility (melting point) was noted. Further consideration utilizing multiple linear regression models afforded correlations based on molecular properties. Regression models, containing melting point and log P (or molar volume) resulted in promising correlations having average absolute errors of 0.43 log units, or a factor of 2.69.     

One-Year Study in Dogs of the Toxicity of HFA-134a by Inhalation

Abstract

HFA-134a, a chlorine-free hydrofluoroalkane, was administered for 1 h daily to beagle dogs by means of a system for inhalation by face mask. In this 1-yr study, animals received atmospheric air, air containing an additional 12% nitrogen, or air containing a nominal 12% HFA-134a for 376 or 377 days. HFA-134a was rapidly absorbed into and cleared from the blood. There were no treatment-related clinical signs or effects on body weight, food consumption, ophthalmoscopy, heart function, respiratory rate, pulse rate, haematology, blood biochemistry, urine analysis, or postmortem findings. HFA-134a was considered to be nontoxic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhaler formulations.     

Twenty-eight-day Double-blind Safety Study of an HFA-134a Inhalation Aerosol System in Healthy Subjects

A 28-day double-blind parallel group study has been conducted to compare the safety and tolerability of HFA-134a, a chlorofluorocarbon-free propellant in a pressurized metered-dose inhaler (MDI A), with a chlorofluorocarbon propellant (MDI C). Sixteen subjects were randomly assigned to receive one of the two MDIs, either four inhalations four times per day for 14 days or eight inhalations four times a day for 14 days, and were then crossed over to the alternative exposure regime with the same propellant for the next 14-day period. No clinically significant changes occurred in blood pressure, heart rate, electrocardiograms, pulmonary function (FEV₁, FVC, FEF_25–75%), haematology or serum chemistry. One subject in the MDI A group had elevated eosinophil counts throughout the study; there were no other remarkable clinical laboratory data. Fifty six adverse events were related to the study propellants; 34 of these occurred in the MDI C group and 22 in the MDI A group. For each adverse event no statistically significant differences were detected between propellant systems or between exposure levels. The most frequent adverse event was headache, which was reported by four subjects with each propellant system. Blood samples for HFA-134a in the MDI A group were collected on day 28 to measure systemic absorption. Blood levels of HFA-134a were detected in all subjects given this propellant within 1 min post-exposure, and these levels decreased to one-tenth of the original value by 18 min after the start of exposure. The safety and tolerability of an HFA-134a chlorofluorocarbon-free system was demonstrated over 28 days of exposure in healthy subjects. These negative results are clinically important because they indicate it will be safe to proceed with the study of this chlorofluorocarbon-free system in asthmatic patients.     

Acute safety of the CFC-free propellant HFA-134a from a pressurized metered dose inhaler

The acute safety of the alternative chlorofluorocarbon-free (CFC-free) propellant HFA-134a from a pressurized metered-dose inhaler (MDI) was assessed in 12 healthy male subjects according to a double-blind, randomized, crossover design. On each of three consecutive days, cumulative doses of 1, 2, 4, 8 and 16 inhalations were administered 30 min apart from one of three MDIs. The three MDIs contained either the HFA-134a CFC-free system without drug (HFA-Placebo), the CFC-free system with salbutamol sulphate (HFA-Salbutamol), or a conventional CFC propellant mixture without drug (CFC-Placebo). Pulmonary function (FEV₁, FEF_25–75%), cardiovascular performance (heart rate and blood pressure), objective tremor measurements and serum potassium were measured after each incremental dose.Similar responses for pulmonary function, cardiovascular performance, tremor and serum potassium were observed between the HFA-Placebo and CFC-Placebo groups. No statistically significant difference was seen in change from baseline of any parameter between the two propellant systems. The administration of HFA-Salbutamol produced statistically significant dose-related increases in heart rate, systolic blood pressure and tremor and a significant dose-related decrease in serum potassium; these responses were expected based on cumulative doses of active drug. Blood samples for HFA-134a analysis were collected to measure systemic absorption of this propellant. Levels of HFA-134a between 200 and 700 ng · ml^–1 were detected in all subjects given the CFC-free system. This study shows that acute inhalation of HFA-134a in a CFC-free system is as safe as a CFC propellant system. Salbutamol sulphate in the CFC-free system can be delivered in a dose-linear fashion, without any noticeable change in the safety profile of active drug.     

Characterization of Suspension-Based Metered Dose Inhaler Formulations Composed of Spray-Dried Budesonide Microcrystals Dispersed in HFA-134a

PURPOSE: To assess the physicochemical characteristics and aerosol properties of suspensions of lipid-coated budesonide microcrystals dispersed in HFA-134a. METHODS: Lipid-coated budesonide microcrystals were prepared by spray-drying an emulsion-based feedstock. Physicochemical characteristics of spray-dried particles were assessed by electron microscopy, laser diffraction, and differential scanning calorimetry. Purity and content were determined by reverse-phase HPLC. Particle aggregation and suspension stability were assessed visually, and aerosol performance was assessed by Andersen cascade impaction and dose content uniformity. RESULTS: Spray-drying of micronized budesonide microcrystals in the presence of phospholipid-coated emulsion droplets results in the production of low-density lipid-coated microcrystals with low surface energy. These spray-dried particles form stable suspensions in HFA-134a. This translates into good uniformity in the metered dose across the contents of the inhaler and acceptable aerodynamic particle size distributions (MMAD = 3.2 to 3.4 microm). The formulation was observed to maintain its performance over 6 months at 40 degrees C/75% RH and 16 months at 25 degrees C/60% RH. No effect of storage orientation was observed on the content of first sprays following storage (i.e., no Cyr effect). The fine particle dose was found to be linear out to suspension concentrations of about 2% wt/vol, and FPD(4.7 microm) values approaching 400 microg can be delivered in a single inhalation. CONCLUSIONS: Engineered particles comprised of lipid-coated microcrystals may provide an acceptable alternative formulation technology for metered dose inhalers in the new hydrofluoroalkane propellants.     

Respiratory deposition patterns of salbutamol pMDI with CFC and HFA-134a formulations in a human airway replica.

This paper describes a technique that uses a well-defined human airway replica and gamma counting as a standard method for evaluating and comparing the performance of medical inhalers and spacers. High-fidelity replicas reproduced as needed from master casts made from human cadavers include the oropharyngeal cavity, larynx, trachea, and five to nine generations of bronchi. Deposition in the small airways and alveoli region of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. Deposition patterns in the respiratory tract replica were obtained by using radiolabel in the medical inhaler and by gamma scintigraphy. This technique was used to determine respiratory deposition patterns of salbutamol in a pressurized metered dose inhaler (pMDI) with chlorofluorocarbon (CFC, in-house formulation) and HFA-134 formulations (Proventil hydrofluoroalkane [HFA]). At an inspiration flow of 30 L/min, patterns in the salbutamol/CFC formula showed a high deposition in the oropharyngeal airway (78%) and a 16% deposition in the lung, similar to in vivo measurements reported in the literature. However, the salbutamol/HFA formula showed lower oral deposition (56%) but higher lung deposition (24%). The difference in the oral deposition patterns may be attributed to lower initial spray velocity, initial droplet evaporation rate, and possibly initial droplet sizes of Proventil HFA. The small orifice diameter (0.25 mm) of the Proventil HFA actuator produced a softer plume with a smaller impact force, resulting in lower oropharyngeal deposition. Cascade impactor measurements showed similar aerodynamic particle size distribution of the CFC and HFA formulations. We also showed that using spacers in the Proventil HFA resulted in a lower oropharyngeal deposition and higher lung deposition, indicating beneficial effects. Comparison of oropharyngeal deposition and those predicted by artificial throats used in the impactor measurements showed that, in general, the artificial throat predicted a lower deposition.     

Beclomethasone relative availability of oral versus inhaled beclomethasone dipropionate from an HFA-134a metered dose inhaler

3M has formulated a new chlorofluorocarbon-free (CFC-free) beclomethasone dipropionate (BDP) metered-dose inhaler (MDI) with the use of the propellant HFA-134a (HFA). Lung deposition studies demonstrated that the HFA BDP MDI delivers to the lungs approximately 56% of the BDP dose (ex-adaptor), a substantially higher percentage than the 5–30% delivered by conventional CFC BDP MDIs. As new sensitive bioanalytical methods are becoming available to quantitate systemic levels of inhaled corticosteroids, pharmacokinetic evaluations are emerging as sensitive and reproducible methods that can be used as a complement to the data obtained from lung deposition studies to assess and compare the performance of MDIs. The present study was designed to determine the beclomethasone (BOH) availability of oral BDP relative to inhaled HFA BDP as a first step to alloy MDI product comparisons in the future. Forty mild asthmatic patients completed this open-label, randomized, single-dose, two-period crossover study. Each patient received an oral dose of BDP (0.2, 0.5, 1, 2 or 5 mg) in one period and an inhaled dose of BDP (0.2 or 0.8 mg) in the other period, with four patients allocated to each of ten different treatment sequences. The BOH availability of orally administered BDP was approximately 40% relative to inhaled HFA BDP. In addition, the fraction of an oral dose that reaches the systemic circulation was estimated from the 40% relative availability and previous lung deposition data to be 0.26. These estimated pharmacokinetic parameters will be used in the future to further characterize the pharmacokinetics of inhaled BDP and to compare the performance of different MDI products. © 1998 John Wiley & Sons, Ltd.     

Deviation from linearity of drug solubility in ethanol/water mixtures

A new empirical function that describes the deviation from linearity of solubility of a drug in an ethanol/water matrix is applied to the experimental data for 51 compounds. The proposed model is a more accurate predictor of the co-solvent solubility profile than a general third order polynomial with the same number of parameters. Both the root mean square error and average absolute error for the proposed model are significantly lower than those of existing models. The model also accurately predicts the fraction of co-solvent that gives maximum solubility (fmax).     

灰黄霉素在含共溶剂丙酮的超临界CO2中溶解度的测定和关联

动态法测定了灰黄霉素在不同的操作温度、压力以及共溶剂丙酮浓度下在超临界CO2中的溶解度.用修正的PR状态方程关联了三元系统的溶解度模型,效果较好.     

Dependence of solute solubility parameters on solvent polarity

In nonpolar solvents a solute may self-associate through polar interactions, exposing its nonpolar surface to a solvent with a low solubility parameter, delta 1. In polar solvents a solute is solvated, presumably, by the polar groups of the solvent. This "chameleonic" effect results in different solubility parameters for a solute, depending on the polarity of the solvent. This report presents data for solute solubility parameters in solvents of variable polarity and gives suggestions for dealing with the chameleonic effect associated with solute-solvent interaction.     

Bilinear model for the prediction of drug solubility in ethanol/water mixtures

A new bilinear function that accounts for the disparity between the log-linear and parabolic models for cosolvent solubilization is presented, where ethanol was used as the model cosolvent. This accounts for both the initial and terminal slopes in the ethanol/water solubility profiles of semi-polar solutes. The proposed model has only two fitted parameters sigmaA and sigmaB, which represent the initial and terminal asymptotes in the solubility profiles. The bilinear function can also model the ethanol/water solubility profile more accurately than the log-linear model and a general parabolic model.     

Comparison of various cosolvency models for calculating solute solubility in water-cosolvent mixtures

Previously published cosolvency models are critically evaluated in terms of their ability to mathematically correlate solute solubility in binary solvent mixtures as a function of solvent composition. Computational results show that the accuracy of the models is improved by increasing the number of curve-fit parameters. However, the curve-fit parameters of several models are limited. The combined nearly ideal binary solvent/Redlich-Kister, CNIBS/R-K, was found to be the best solution model in terms of its ability to describe the experimental solubility in mixed solvents. Also resented is an extension of the mixture response surface model. The extension was found to improve the correlational ability of the original model.     

Measurement and correlation of solubility data for albendazole in ten pure solvents and two binary solvent systems from 278.15 K to 323.15 K

The equilibrium solubility of albendazole (ABZ) in ten single solvents and two binary solvent mixtures of different ratio was measured by a typical static method combined with ultraviolet (UV) spectrophotometry within the temperature range from 278.15 K to 323.15 K. Meanwhile, the modified Apelblat model, Van't Hoff equation and λh equation were used to correlate the solubility data of ABZ in pure solvent, the modified Apelblat model, λh equation, Sun model, GSM equation and NRTL model were used to correlate the solubility data of ABZ in binary mixed solvent, the 100RD, 100ARD, 103RMSD and 103ORMSD values of the above models were calculated respectively. The results show that the experimental data of six models have a good correlation with the calculated data. Especially, the Van't Hoff equation in pure solvent has the best fitting effect, and the GSM equation in binary mixed solvent has the best fitting effect. Additionally, the Van't Hoff equation was used to calculate and evaluate the thermodynamic properties of the ABZ dissolution process, including enthalpy (ΔdisH), entropy (ΔdisS) and Gibbs free energy (ΔdisG).     

Estimation of the ethanol/water solubility profile from the octanol/water partition coefficient

While the ethanol/water solubility profiles of very polar and very non-polar drugs are monotonic, many semi-polar drugs show a maximum solubility at an ethanol volume fraction (f(max)) between 0 and 1. A sigmoidal relationship was observed between the value of f(max) and the log of the octanol/water partition coefficient (logK(ow)) of the solute. This relationship reasonably predicts the value of the volume fraction of ethanol that gives maximum solubility (f(max)). Combining this sigmoidal relationship with the previously reported linear relationship between the logK(ow) and the initial slope of the plot of log solubility versus ethanol composition [Li, A., Yalkowsky, S.H., 1994. Solubility of organic solutes in ethanol/water mixtures. J. Pharm. Sci. 83, 1735-1740] enables the estimation of the total ethanol/water solubility profile.     

Effects on lung function, symptoms, and bronchial hyperreactivity of low-dose inhaled beclomethasone dipropionate given with HFA-134a or CFC propellant.

The aim of this study was to compare the efficacy of BDP 200 microg bid via metered dose inhaler, using HFA-134a (Chiesi Farmaceutici S.p.A., Parma, Italy) versus CFC (Becotide, Allen & Hanburys, U.K.) as a propellant. 172 adult patients (86 in each group) with stable mild persistent asthma who completed a 7-day run-in period were randomized to receive a 6-week treatment in a double-blind, double dummy, parallel-group design; 164 patients completed the study. Morning and evening PEFR, use of rescue salbutamol, number of day-time and night-time asthma attacks, number of night-time awakenings and clinical symptoms were recorded daily on a diary card. Pulmonary function tests (FEV(1), FVC, PEFR, and MEF(50)) were measured at the clinic before and after the 1-week run-in period, and after 3 and 6 weeks of treatment. A challenge test with inhaled methacholine was completed at baseline and at the end of the treatment period to assess potential bronchial hyper-reactivity in a subgroup of subjects (n = 65; 34 HFA, 31 CFC). In accordance with asthma of mild severity (FEV(1) predicted over 90% in both groups), a small improvement in lung function compared to baseline was seen for both treatments, significantly for FEV(1) in BDP HFA and MEF(50) in both groups. The two formulations of BDP had similar efficacy for the primary outcome variable morning PEFR (ITT population mean difference 5.8 L/min; C.I. -4.9 to +16.5) as well as for the secondary outcomes of evening PEFR and clinic FEV(1). There were small improvements in methacholine PD(20) and PC20 in both groups, with no significant difference between treatments. A total of 22 and 19 drug-related adverse events were reported in the BDP HFA and CFC groups, respectively; most events were of seasonal nature or were local effects due to the use of inhaled corticosteroids. It can be concluded that the newly developed formulation of BDP given via HFA-134a seems to provide similar asthma control, compared with the same low daily dose of the active drug delivered via CFC. Further studies are needed using higher doses in moderate to severe asthma to confirm these preliminary findings.     

A study comparing the clinical pharmacokinetics, pharmacodynamics, and tolerability of triamcinolone acetonide HFA-134a metered-dose inhaler and budesonide dry-powder inhaler following inhalation administration

The impending phaseout of chlorofluorocarbons as propellants in pressurized metered-dose inhalers used in the treatment of asthma has resulted in the development of alternative devices to deliver drug to the pulmonary airways. These alternative devices include metered-dose inhalers using environmentally friendly hydroflurocarbon propellants and breath-actuated dry-powder inhalers. The purpose of this study was to compare the single- and multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of a newly developed hydroflurocarbon formulation of triamcinolone acetonide (Azmacort HFA 225 mcg Inhalation Aerosol) to that of the dry-powder formulation of budesonide (Pulmicort Turbuhaler 200 mcg). This three-way crossover study used 18 normal healthy subjects each receiving a 675 mcg dose of triamcinolone acetonide, 600 mcg dose of budesonide, or placebo twice a day for 5 days. Serial plasma samples were collected after the first and last dose of test medication for pharmacokinetic analysis. Pharmacodynamics were assessed by changes in hypothalamic-pituitary-adrenal axis function as measured by 8 a.m. serum cortisol, 24-hour overnight serum cortisol AUC(0-24), and 24-hour urinary-free cortisol after the last evening dose of test drug. Tolerability was assessed through physical examinations, vital signs, 12-lead ECG, routine clinical labs, and adverse events recording. Both compounds were systemically absorbed. However, no significant drug accumulation was noted with chronic dosing. Chronic dosing did result in a statistically significant 20% reduction in basal 24-hour serum cortisol AUC(0-24) for both compounds. There were no clinically significant abnormalities in physical examination, vital signs, 12-lead ECG, or routine clinical labs noted during the study. Overall, the study drugs were well tolerated, with adverse events characterized as mild to moderate in severity.     

An improved empirical model to calculate solute solubility in supercritical carbon dioxide

To provide more accurate solubility predictions in supercritical carbon dioxide (SC-CO2) using an empirical model employing density as an independent variable, the density of SC-CO2 at different temperatures and pressures has been calculated and compared with experimental densities. The average percentage deviation (APD) has been determined as an accuracy criterion and the obtained APD for the equations studied were between 1.3 (+/-1.4)-11.6 (+/-8.9)%. To show the effects of density values on solubility prediction, the solubility of 18 drug compounds in SC-CO2 has been calculated using an empirical equation with respect to temperature, pressure and density. The APD values for correlative analysis was 8.5 (+/-5.8)% for the most accurate density values calculated by BACK equation of state. A minimum number of experimental data (i.e. 6 points) has been used to train the model then the solubility at other temperatures and pressures has been predicted and the APD value for the most accurate densities obtained was 14.2 (+/-9.4)%. This prediction error could be considered as acceptable when it is compared with RSD values for repeated measurements (approximately 10%) and the proposed predictive method could be employed in industry to calculate the solubility of a drug using a limited number of experimental data.     

The effect of proton-acceptor sites of the solute on its solubility in proton-donor solvents

The solubilities of five solid ketones and two esters are predicted in common organic nonelectrolyte solvents using the solubility equation derived from the mobile order theory. In the framework of this theory, the formation of solute-solvent hydrogen bonds is treated on the basis of standard stability constants. Two different values characterizing the ketone-alcohol and the ester-alcohol hydrogen bonds, respectively 170 and 110 cm³/mol, have been determined. The formation of specific molecular interactions brings about a net increasing of the solubility without modifying the values of the other contributions relevant to the solution process. Using the predetermined values of the stability constants, the solubility equation is then successfully applied to predict the solubility of testosterone propionate in 28 solvents including alcohols and water from the sole knowledge of its solubility in hexane.     

Deviations of drug solubility in water-cosolvent mixtures from the Jouyban-Acree model--effect of solute structure

Deviations of the predicted solubilities using the Jouyban-Acree model from experimental data were correlated to the structural descritptors of the drugs computed by HyperChem software. The proposed models are able to predict the solubility in water-cosolvent mixtures and reduced the mean percentage deviations (MPD) of predicted solubilities from 24%, 48%, and 53% to 16%, 33% and 38%, respectively for water-propylene glycol, water-ethanol and water-polyethylene glycol 400 mixtures, with the overall improvement in prediction capability of the model being approximately 13%.