Measurement and correlation of solute solubility in HFA-134a/ethanol systems

The goals of this study were to determine the solubility values of solid organic solutes in pure HFA-134a and in HFA-134a/ethanol cosolvent systems (0-20%, w/w), and to investigate the relationship between these solubilities and a solute's physico-chemical properties. A direct inject on-line HPLC method was used to determine the solubility of 21 solutes in HFA-134a/ethanol. The samples were allowed to equilibrate for at least 48h. The filtered sample was injected directly on an analytical HPLC column through a manual injector interface, and analyzed at an appropriate solute wavelength via HPLC. The solutes display diverse physico-chemical properties and yielded solubility values that ranged over four orders of magnitude. In general, a linear-linear solubility relationship was observed as the fraction of ethanol increased. The effects on solubilization ranged from 1.3 to 99.4 times when 20% (w/w) ethanol was introduced, relative to pure HFA-134a. A regression equation utilizing a solute's hydrogen bonding potential resulted in a significant correlation to the slope obtained from a linear model for solubility in HFA-134a with 0-20% (w/w) ethanol, and may be useful for pre-formulation studies.     

CFC replacements: safety testing, approval for use in metered dose inhalers.

HFA-134a and HFA-227 (chlorine free hydrofluoro-alkanes) are at present in extensive nonclinical safety testing sponsored by two joint research consortia (IPACT-I, IPACT-II) of companies interested in metered dose inhalers (MDI). The rationale for toxicity testing of these CFC replacements is to predict safety of their use as drug propellants in MDI. Frequency of use, intervals and systemic exposure levels are key parameters. Intact animals and in-vitro systems repeatedly exposed to multiples of patient doses, under conditions comparable to human administration should not show adverse reactions. With an emphasis different from non-U.S. Health Authorities, the U.S. FDA insists on proof of toxic effects which may require excessive doses. This principle is questioned for essentially inert gases such as CFCs and HFA-134a and HFA-227 which only through the effects of oxygen deprivation at unreasonably high concentrations of the inhaled propellant/air mixture indirectly cause mild toxic effects in animals. Provided that no intrinsic toxic effects will be detected, chances are good that these CFC replacements will eventually be approved. In view of the estimated 5-year testing time frame and the risks involved, CFCs should remain available for MDI for some time in the future.     

A comparison of two methods to determine the solubility of compounds in aerosol propellants

A new on-line reverse phase HPLC method for determining the solubility of compounds in propellant based metered dose inhaler (MDI) formulations was compared with a conventional method. The new method employs a direct injection from a MDI vial into the needle injector port of a manual injector. To evaluate the two methods, beclomethasone dipropionate (BDP), 5,5-diphenyl hydantoin and 3,3'-diindolylmethane, were used as model compounds in propellant HFA-134a. Comparison was performed by analyzing known and unknown concentrations of BDP in various combinations of HFA-134a and ethanol. In addition, the solubility of 5,5-diphenyl hydantoin and 3,3'-diindolylmethane were determined in HFA-134a using both the new and the conventional methods. The two methods were found to be in good agreement with each other, with the new direct injection technique offering enhanced precision and accuracy along with considerable reduction in analysis time.     

Solubility, melting point and salting-out relationships in a group of secondary amine hydrochloride salts

The solubilites of eight hydrochloride salts of some alpha adrenergic agonists, and beta adrenergic agonist/blocker drugs were determined in water at 25°C. An inverse relationship was observed between log X⁺ and the melting points of the salts where X⁺ is the mole fraction solubility of drug. The entropy of fusion values were not constant, as suggested by the observed log solubility-melting point correlation, and ranged from 16 to 26 cal K⁻¹ mol⁻¹. It is therefore unlikely that crystal forces alone are responsible for the observed relationship between log X⁺ and melting point. Setchenow salting-out constants were determined from the solubilities of the hydrochloride salts in sodium chloride-water and were found to be greatest for those compounds that possessed the lowest aqueous solubility and highest melting point. The number of aromatic rings and aromatic ring substituents also appear to have a significant influence on the values of the salting-out constants.     

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.     

Reformulation of Stmerin® D CFC formulation using HFA propellants

Stmerin^® D was reformulated using hydrofluoroalkanes (HFA-134a and HFA-227) as alternative propellants instead of chlorofluorocarbons (CFCs), where the active ingredients were suspended in mixed CFCs (CFC-11/CFC-12/CFC-114). Here, we report the suspension stability and spray performance of the original CFC formulation and a reformulation using HFAs.

We prepared metered dose inhalers (MDI) using HFAs with different surfactants and co-solvents, and investigated the effect on suspension stability by visual testing. We found that the drug suspension stability was poor in both HFAs, but was improved, particularly for HFA-227, by adding a middle chain fatty acid triglycerides (MCT) to the formulation. However, the vapor pressure of HFA-227 is higher than a CFC mixture and this increased the fine particle dose (FPD). Spray performance was adjusted by altering the actuator configuration, and the performance of different actuators was tested by cascade impaction. We found the spray performance could be controlled by the configuration of the actuator. A spray performance comparable to the original formulation was obtained with a 0.8 mm orifice diameter and a 90° cone angle. These results demonstrate that the reformulation of Stmerin^® D using HFA-227 is feasible, by using MCT as a suspending agent and modifying the actuator configuration.     

Surfactant solubility and aggregate orientation in hydrofluoroalkanes

PURPOSE: To find surfactants soluble in the two hydrofluoroalkane (HFA) propellants, HFA-134a and HFA-227ea; to compare surfactant solubility in the two propellants with those in 2H,3H-decafluoropentane (DFP) in order to assess latter's suitability as a liquid model propellant and to investigate surfactant aggregation and aggregate orientation in HFAs. METHODS: To assess surfactant solubility, HFA was added to a known amount of surfactant until dissolution was visibly apparent. An iodine solubilization method was used to determine surfactant aggregation behaviour in DFP. Fluorescence spectroscopic investigations on the surfactant orientation in aggregates were carried out in HFAs using a microviscosity sensitive fluorescent probe (1,3-dipyrenylpropane). The aim was to assess viscosity changes in the microenvironment of this lipophilic probe upon incorporation into surfactant aggregates. RESULTS: Soluble surfactants could be found among the polyoxyethylene-ethers and POE-PPO-block copolymer surfactants. Solubility in DFP appears to correlate with solubility in HFA-134a, but not HFA-227ea. Iodine solubilization indicates micellization of Brij 30 in DFP at a cmc (type II association behaviour). L-44 in DFP, on the other hand, does not exhibit a well defined cmc, but shows continuous surfactant aggregation (type I association behaviour). The fluorescence spectroscopic studies showed evidence for probe incorporation into surfactant aggregates in HFAs. CONCLUSIONS: DFP proved to be a good model for HFA-134a only. An L1-aggregate orientation was shown for surfactants in HFAs and is in marked contrast to the chlorofluorocarbon propellant where a L2-aggregate orientation exists.     

Prodrug to probe solution HFA pMDI formulation and pulmonary esterase activity

A novel salbutamol prodrug was synthesised. Solubility in HFA-134a and susceptibility to rat lung homogenate, blood and plasma esterase enzymes were investigated. Whereas salbutamol had a very low solubility in HFA-134a, the prodrug was found to be miscible in all proportions. In lung homogenate, the prodrug hydrolysed with a half-life of 45 min, re-generating approximately 17% of expected salbutamol after 8 h incubation. The use of a solution pMDI for pulmonary delivery of the salbutamol prodrug is predicted to result in liberation of salbutamol in the lungs following in vivo hydrolysis by lung esterases.     

Contribution of solid-state properties to the aqueous solubility of drugs.

This study investigates the influence of the solid-state properties melting point (T(m)), enthalpy of melting (DeltaH(m)) and entropy of melting (DeltaS(m)) of a drug on its intrinsic solubility (S(0)). For this purpose, 26 chemically and structurally diverse drugs covering the oral drug space were selected and the S(0), T(m), DeltaH(m) and DeltaS(m) were determined experimentally. The influence of T(m), DeltaH(m) and DeltaS(m) on S(0) was studied using regression analysis. The overall improvement of the predictions were 0.3 log units, however, five compounds (astemizole, glyburide, fenbufen, gliclazide and griseofulvin) were improved by more than one log unit. T(m) and DeltaH(m) had a larger effect than DeltaS(m) on the solubility predictions. The well-known general solubility equation (GSE) and the Dannenfelser semi-empirical equation for the calculation of DeltaS(m) were evaluated using our data set. While predictions of drug solubility obtained using the GSE were acceptable, the use of the experimental DeltaS(m) values instead of the constant 56.5 J mol(-1)K(-1) improved the accuracy of the prediction. The Dannenfelser equation underestimated the DeltaS(m) for most compounds with on average 15 J mol(-1)K(-1). Our results show that solid-state properties should be considered for improved performance of future models for prediction of drug solubility. In addition our study provides accurate experimental data on intrinsic solubility for 26 compounds, supplying a useful external data set for validation of drug solubility models.     

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.     

The Equivalent Bronchodilator Effects of Salbutamol Formulated in Chlorofluorocarbon and Hydrofluoroalkane-134a Metered Dose Inhalers on the Histamine-Induced Pulmonary Response in Dogs

Purpose. The bronchodilator effect of salbutamol formulated in hydrofluoroalkane-134a (HFA-134a), a Chlorofluorocarbon (CFC)-free propellant for metered dose inhalation (MDI) devices, was compared with that of salbutamol formulated in CFC in anesthetized dogs. Methods. Bronchospasms were induced by the intravenous injection of histamine, and bronchial resistance was measured by the method of Konzett and Rossler. Results. While the placebo vehicles (HFA-134a and CFC propellants) had no significant effect on histamine-induced bronchospasms, the salbutamol/HFA-134a and salbutamol/CFC MDI formulations had equivalent dose-related inhibitory effects. Conclusions. These data indicated that salbutamol formulated in HFA-134a and that in CFC propellant are bioequivalent.     

Issues surrounding MDI formulation development with non-CFC propellants.

Reformulation of metered-dose inhalers (MDIs) without the use of chlorofluorocarbon (CFC) propellants presents numerous obstacles because there are no alternative propellants that can serve as immediate replacements for pharmaceutical use. Hydrofluorocarbons (HFCs), hydrochlorofluorocarbons (HCFCs) and hydrocarbons (HCs) are all under consideration as possible alternatives for CFC propellants. However, no single propellant or combination of propellants has been identified with all of the physical-chemical properties of CFCs. Based on their zero ozone depletion potentials, relatively low global warming potentials, non-flammabilities, densities, and vapor pressures, HFA-134a and HFA-227 are the most attractive replacement propellants identified to date. Yet, their use in MDIs will still require: (1) identification of a metering valve with propellant and formulation-compatible gaskets, (2) use of current suspending agents at levels much lower than in present MDIs or identification (and characterization) of new suspending agents, and (3) modification of existing manufacturing technologies. Demonstration of acceptable final product stability, safety and efficacy will be necessary prior to submission to worldwide registration authorities.     

Design, synthesis, and biological activity of 1,3-disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase of increased water solubility

The soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in blood pressure regulation and inflammation. 1,3-Disubstituted ureas are potent inhibitors of sEH that are active both in vitro and in vivo. However, their poor solubility in either water or lipid reduces their in vivo efficacy and makes them difficult to formulate. To improve these physical properties, the effect of incorporating polar functional groups into one of the alkyl chains was evaluated on their inhibitor potencies, water solubility, octanol/water partition coefficients (log P), and melting points. No loss of inhibition potency was observed when a polar functional group was incorporated at least five atoms ( approximately 7.5 A) from the central urea carbonyl. In addition, the presence of a polar group at least 11 atoms away from the urea carbonyl group for the mouse and human sEHs, respectively, did not alter the inhibitor potency. The resulting compounds have better water solubility and generally lower log P values and melting points than nonfunctionalized liphophilic ureas. These properties will make the compounds more bioavailable and more soluble in either water- or oil-based 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.     

Estimation of the ideal solubility (crystal–liquid fugacity ratio) of organic compounds

Melting point, entropy of melting and heat capacity of melting are required for the calculation of the ideal solubility of a solid solute via the Clausius–Clapyron equation. This article reviews the published approximations of estimating entropy and heat capacity of melting. By comparing the available experimental results to calculated values the authors attempt to identify the best estimation of the ideal solubility and crystal–liquid fugacity ratio for organic compounds. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1100–1106, 2010     

Application of Thermodynamic Phase Diagrams and Gibbs Free Energy of Mixing for Screening of Polymers for Their Use in Amorphous Solid Dispersion Formulation of a Non-Glass-Forming Drug

The objective of the present investigations was to assess the use of thermodynamic phase diagrams and the Gibbs free energy of mixing, ΔG_mix, for the screening of the polymeric carriers by determining the ideal drug-loading for an amorphous solid dispersion formulation and optimum processing temperature for the hot-melt extrusion of a non-glass-forming drug. Mefenamic acid (MFA) was used as a model non-glass-forming drug and four chemically distinct polymers with close values of the solubility parameters, viz. Kollidon® VA64, Soluplus®, Pluronic® F68, and Eudragit® EPO, were used as carriers. The thermodynamic phase diagrams were constructed using the melting point depression data, Flory-Huggins theory, and Gordan-Taylor equation. The Gibbs free energy of mixing was estimated using the values of the drug-polymer interaction parameter, χ, and Flory-Huggins theory. The rank order miscibility of MFA in the four polymeric carriers estimated based on the difference in the values of their solubility parameters, Δδ, did not correlate well with the thermodynamic phase diagrams and Gibbs free energy plots. The study highlights the limitation of using the solubility parameter method in screening the polymeric carriers for poorly glass-forming drugs and reiterates the applicability of thermodynamic phase diagrams and Gibbs free energy plots in determining the ideal drug-loading and optimum processing temperature for hot-melt extrusion.     

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.     

Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters

Purpose  The amorphous form of a drug may provide enhanced solubility, dissolution rate, and bioavailability but will also potentially crystallize over time. Miscible polymeric additives provide a means to increase physical stability. Understanding the miscibility of drug–polymer systems is of interest to optimize the formulation of such systems. The purpose of this work was to develop experimental models which allow for more quantitative estimates of the thermodynamics of mixing amorphous drugs with glassy polymers. Materials and Methods  The thermodynamics of mixing several amorphous drugs with amorphous polymers was estimated by coupling solution theory with experimental data. The entropy of mixing was estimated using Flory–Huggins lattice theory. The enthalpy of mixing and any deviations from the entropy as predicted by Flory–Huggins lattice theory were estimated using two separate experimental techniques; (1) melting point depression of the crystalline drug in the presence of the amorphous polymer was measured using differential scanning calorimetry and (2) determination of the solubility of the drug in 1-ethyl-2-pyrrolidone. The estimated activity coefficient was used to calculate the free energy of mixing of the drugs in the polymers and the corresponding solubility. Results  Mixtures previously reported as miscible showed various degrees of melting point depression while systems reported as immiscible or partially miscible showed little or no melting point depression. The solubility of several compounds in 1-ethyl-2-pyrrolidone predicts that most drugs have a rather low solubility in poly(vinylpyrrolidone). Conclusions  Miscibility of various drugs with polymers can be explored by coupling solution theories with experimental data. These approximations provide insight into the physical stability of drug–polymer mixtures and the thermodynamic driving force for crystallization.