Solubility Behaviour of Aripiprazole in Different Solvent Systems

Introduction

Cosolvents are frequently used to increase solubility when a drug candidate's aqueous solubility (AS) is insufficient to allow for solution formulations.¹ The definition of solubilization would be the process of introducing one or more amphiphilic components to a substance that is ordinarily insoluble or very marginally dissolves in a precise solvent to generate a firm solution.^2,3 Dissolving of poorly water-soluble drug in formulation progress is a significant phenomenon. Cosolvency, hydrotrophy, buffers, temperature modification, surfactants besides complexation are the common solubility enhancement pharmaceutical practices.⁴ The use of a cosolvent is a widespread strategy in the formulation of oral, nasal, and ophthalmic liquids. Modi reported the impact of polyethylene glycol (PEG) in boosting the aqueous solubility (AS) of Valdecoxib.⁵ Chertkoff MJ studied benzoic acid solubility in numerous solvent blends.⁶ Despite its effectiveness, cosolvency may be difficult to use due to its concentration limit and precipitation upon dilution. Researchers have also explored the use of cosolvents in conjunction with buffers, surfactants, and cyclodextrins.⁷

Aripiprazole (ARP) is a distinctive antipsychotic medication prescribed to manage schizophrenia. ARP seems to facilitate antipsychotic properties via partial agonism. Chemically ARP is 7-{4-[4-(2,3-dichlorophenyl) piperazin-1-yl] butoxy}-1,2,3,4-tetrahydroquinolin-2-one.^8,9

Since the ARP is very weakly soluble (BCS Class-II), it is imperative to increase its solubility with an appropriate method. The cosolvency technique must be investigated, despite the substantial research that has been done utilizing other solubilization performances. The current study set out to analyze how cosolvents affected solubility of ARP. Cosolvents selected were hexane, ethylacetate, dioxane, ethanol, propyleneglycol, PEG 400 and glycerin.

Materials and Methods

ARP was procured from Hetero Labs, Jadcherla, Telangana, India as a complimentary sample. The entire work was conducted using double-distilled water that had been prepared in the lab. Other chemicals used were of research grade. The statistical functions of MS Excel program were used for analysis of the experimental data. The MS Office Excel (2022) was used to create graphs. Standard statistical techniques were used to calculate various statistical parameters.

Drug Estimation

ARP estimation was made in 0.1 N HCl solutions at λ_max of 248.6 nm using UV-Vis spectrophotometer (1700 Shimadzu, Japan). Calibration curves of ARP complied with Beer-Lambert’s law (5-35 µg/mL), R² = 0.999.

Solubility Determination

Solvent or solvent blends (10 mL) were placed in 50 mL stoppered volumetric flasks. ARP (100 mg) was then directly added to each flask. The flasks were operated using cryostatic constant temperature reciprocating shaker bath (Research and Test Equipments, Bangalore, India), set at 25±1°C for one day to acquire equilibrium and the equilibrium was confirmed by comparing numerous samples at day 1 and day 2. After day 1, the samples were collected, filtered, and diluted appropriately.^10,11 At 248.6 nm, samples were examined. Each experiment involving solubility was run in triplicates.

Formulation Development

Based on the solubility data obtained with cosolvents, certain formulations can be proposed. Preliminary attempts were made to design liquid orals and injections at 2 mg and 5 mg doses, avoiding all other excipients.

Precipitation on Dilution

Formulations designed based on the solubility data, particularly when cosolvents were used, tend to undergo precipitation provided the drug solubility falls below saturation solubility level. This might not take place with all the formulations. Hence the prepared formulations were diluted with water 100 times, were subjected to observation visually and tested for precipitate formation in UV spectrophotometer.

Results

The solubilities of ARP in biocompatible cosolvents explicitly PEG 400, ethanol, propylene glycol (PG), glycerin, in addition to industrially used organic solvents, hexane, ethyl acetate, dioxane in pharma industry at 25^oC, are reported in Table 1, along with reported dielectric constant values.¹²

The solubility values of ARP in solvent combinations at 25^o C are displayed in Table 2 for biocompatible solvents (ethanol, PG, glycerin, and PEG 400). The solvent mix dielectric constants were computed using expression, ε_mix = ε_ws f_ws + ε_ss f_ss , where ε and f are the dielectric constant and volume fraction, respectively. In addition, the mixture, weaker solvent, and stronger solvent are denoted by the subscripts mix, ws, and ss, correspondingly.¹⁵ Figure 2 demonstrates ARP solubility performance in water-cosolvents (PEG 400, ethanol, PG, and glycerin).

PEG 400 > ethanol > PG > glycerin was the sequence in which the cosolvents showed the highest solubilization power. The increase in solubility was deduced as 2098, 104, 19, and 8 folds for PEG-400, ethanol, PG, and glycerin (100% cosolvent level), respectively.

The equation which describes the exponential reliance of non-polar solute solubility upon cosolvent proportion in a semi-aqueous solution is,

log [D_tot ] = log [D_u] + σ [C]                                                    (1)

where [D_tot] total solubility of ARP, [D_u] ARP water solubility, [C] cosolvent concentration, σ is the cosolvent solubilizing power of the solute.¹⁶

Reduced polarity of the solvent results in elevated solubilization power, thus higher the σ value. As anticipated, ethanol showcased greater solubilization power due to diminished polarity. Model calculations for solubilization power of ethanol are depicted in Table 3a. σ values found using equation (1) for the numerous cosolvents are shown in Table 3b. The fact that drug components prefer to dissolve in non-polar environments over polar (aqueous) ones is evident from this.

Discussion

The solubility behavior of Aripiprazole was investigated using biocompatible solvents such as polyethylene glycol 400 (PEG-400), ethanol, propylene glycol (PG), glycerin, along with pharmaceutically used solvents like dioxane, hexane, and ethyl acetate, both in their pure forms and in various blends.

Solubility in Pure Solvents

The solubilities of ARP in biocompatible cosolvents are investigated. Perusal to the table directs that ARP solubility rises with decline in the dielectric constant, which signifies polarity impact on ARP solubility with cosolvent support. The dielectric constant of the drug in question is assumed to be equal to the corresponding value of the solvents in which it has the greatest solubility.⁶ The impact of polarity on drug solubility in solvent mixtures and pure solvents has been documented in many research papers.

The ARP unveiled poor AS due to its nonpolar nature; it failed to break effectively into the lattice structure of water, hence less AS.¹⁷ Improved ARP solubility in ethanol specifically indicates hydrogen bonding exhibited by it. The interactions were uniform in the selected drug. In hexane, the hydrophobic effects and hydrogen bonding are equally significant, leading to the exclusion of drug molecules, which are compressed as both forces come into play. Some type of self-association of solvent and solute or both might have occurred.¹⁸

Elevated solvent hydrophobicity showcased that the drug solubility rises with rise in hydrophobic property of solvents. Nevertheless, ARP in hexane serves as a prime illustration of how other parameters, besides polarity and hydrophobicity also play a pivotal role in the solubility process.

The experimental octanol-water partition coefficient (log p) of ARP was 4.5519, suggesting good solubility in lipophilic solvents.²⁰ PEG 400 exhibited a spike in solubility, indicating a greater significance of hydrophobic interactions in regulating medicament solubility. Leveraging solubility evidence acquired in the pure solvents, cosolvency technique was implemented to boost the solubility, which is addressed in greater depth below.

Solubility in Mixed Solvent

Systems Water-miscible solvents, routinely utilized in the pharmaceutical sector for solubilization, are deemed biocompatible cosolvents. The stronger solvent is the one that offers predominant ARP solubility (cosolvent), while the weaker solvent is water. In general, solubility improved with a decline in the dielectric constant (blended form).  ARP solubility gradually increased with elevated ethanol proportion (60-100%). Maximum solubilization depends on solute and solvent relative polarity. This consequence arises since the ARP also has polar character to some extent. Furthermore, there are additional elements at play besides the polarity of the solvent and solute. However, influence of ethanol from 0 to 50% was minimal.

Solubility of tetrachlorobenzene, benzoic acid, acetanilide, and phenobarbital increased with increase in propylene glycol.²⁰ Similar result was found with ARP. The degree of solubilization by each cosolvent improved with the decline in the solvent system polarity. Caffeine and theophylline showed bell shaped solubility curve in ethanol-water mix which resembles the solubility of ARP.²¹ Meloxicam and Rofecoxib solubility were directly proportional to PEG 400 concentration, which is in agreement with ARP solubility in PEG 400-water system.¹⁸ However, glycerin exhibited inverse proportionality with the solubility of ARP which was also observed with D, L-phenylalanine.²⁰ Together with water, the cosolvents generated a uniform mixture. Since the cosolvents tend to be less polar than water, it led to diminished polarity in blended form than pure water.²²

The solubility of ARP enhanced due to the fall in aqueous solution polarity. Diminished ARP solubility in less than 50% ethanol-water mixtures may be due to specific solute-solvent interactions. Published cosolvency studies by Miyako Y et al.,²³ Bustamante P et al.,²⁴ and Millard JW et al.,²⁵ primarily examined the (significant) impact of water–cosolvent interactions on the measured solubilization characteristics of multiple drugs.

Solubility Data Implication

The AS of ARP is approximately 0.000126 mg/mL. Thus, ARP solubility is boosted via cosolvency technique as explained earlier. Though cosolvents increased the solubility, attention should be given to selecting the proportion of cosolvents to be used while preparing the formulations, as they were found to produce irritation.

The available ARP tablet doses in pharmaceutical market are 2, 5, 10, 15, 20, and 30 mg. Poorly soluble drugs generally hold hydrophilic-lipophilic balance advantageous to their permeation via GI membranes so that dissolution turns to be the conclusive aspect in the bioavailability of these drugs. The formulation of lipophilic drugs is often delayed by their poor AS, which limits their therapeutic application. It is indispensable to formulate oral liquids of ARP. Since the AS of ARP is less, an effort was made to formulate oral liquids and parenterals. The lowest ARP tablet dose is 2 mg. Hence attempt was made to formulate oral liquids. Thus, 2 mg solutions in 5 mL and 10 mL were made. Injections were formulated in accordance. The injections are typically formulated via minimum volume feasible. Efforts to formulate injections comprising 2 mg in 1 mL or 2 mg in 2 mL were made in the current investigation. An analogous endeavor was undertaken to develop solutions of 5 mg dosage.

Precipitation on Dilution

When the formulation is diluted, the active components in certain products developed with cosolvent-solubilized drugs possibly precipitate.²⁶ This phenomenon can occur in various contexts, including within the bloodstream, in vitro environments, during intravenous infusions, or at intramuscular injection sites. The precipitation of drug particles poses several potential risks. Mechanically, these particles can irritate or obstruct blood vessels, which may lead to complications such as thrombosis or embolism. Additionally, localized high concentrations of the precipitated drug can induce local toxicity, potentially causing tissue damage or adverse reactions at the site of administration. Furthermore, precipitation can significantly reduce the systemic bioavailability of the drug, compromising its therapeutic efficacy.

To mitigate these risks, the prepared injection formulation underwent rigorous testing to detect any precipitate formation. Analytical techniques such as UV spectrophotometry and visual inspection were employed to monitor the stability of the formulation under various conditions. The results indicated that there was no precipitation observed, either upon dilution or after six weeks of storage. This stability suggests that the formulation maintains its solubilized state, ensuring consistent drug delivery and minimizing the risk of adverse effects associated with precipitation.

Conclusion

The impact of each cosolvent to the extent that it affects ARP's solubility is not identical. This might indicate the consequence of a conformational shift in the ARP structures with solvent polarity, meaning that the structures' hydrogen bonds would be preferred by nonpolar media but improbable to occur in powerful hydrogen bonding source like water.

Using seven distinct cosolvents, investigation assessed and related the individual solubility enhancement of ARP. When formulating liquid oral dosage forms in dosages of 2 mg and 5 mg, the selected cosolvents PEG-400, ethanol, PG, and glycerin proved to be the most effective solubilizing cosolvents while offering an acceptable safety profile. PEG-400, PG, and ethanol were discovered to be appropriate for formulating parenteral in the doses of 2 mg and 5 mg. There are various applications for the drug solubility data in organic solvents in pharmaceutical industry.

Conflict of interest

The authors do not have any conflict of interest.

Acknowledgment

The authors would like to express their gratitude to Dr. A P Basavarajappa, Director and Dr. J. H. Mruthyunjaya Principal, Bapuji Pharmacy College, for providing the facilities needed to conduct the research, to Dr. C.V.S. Subrahmanyam, Emeritus Professor for sharing the concept of the project.