Mechanochemical Activation of Olanzapine in Mixed Solid Dispersions: Impact of Excipients on Release and Permeation Rates

Abstract

Background: The key parameters determining the bioavailability of an active pharmaceutical ingredient are its solubility/dissolution rate in physiological fluids and permeability across biological membranes. Highly accurate in vitro prediction of bioavailability is a key issue that typically arises during the development of new drug formulations and the improvement of existing ones.

Objectives: The objective of the present work is to study the dissolution/release and permeation of olanzapine (OLZ) from two- and three-component solid dispersions (SDs) with sulfobutylether-β-cyclodextrin (SBE-β-CD) and several pharmaceutical adjuvants as solubilizing agents.

Methods: Solid dispersions were prepared by mechanical grinding and characterized with X-ray Phase analysis (PXRD), Fourier Transform Infrared (FTIR) and Raman spectroscopy, Differential Scanning Calorimetry (DSC), and Scanning Electron Microscopy (SEM).

Results: Raman spectroscopy was shown to be the best for revealing the interactions of OLZ with SBE-β-CD and γ-aminobutyric acid (GABA) in the three-component SD. The kinetic dependences of OLZ release and diffusion through the cellulose membrane were thoroughly described by quantitative parameters and classified according to the drug release mechanism. Significant improvement of release rate, OLZ concentration, and permeation with SDs compared to the pure OLZ was demonstrated.

Conclusions: It was shown that the selected dispersions were stable when stored under normal conditions but underwent changes upon exposure to elevated temperature and humidity. The nature of these changes was determined by the properties of the components and their mutual interactions.

Introduction

The oral route of drug administration is one of the most common in clinical practice. The effectiveness of an oral active pharmaceutical ingredient (API) depends on its physicochemical properties and the physiology of the gastrointestinal (GI) tract. The most important parameters are stability, solubility, permeability across the intestinal epithelium, and transit time through the gastrointestinal tract segments where maximum absorption occurs. Most marketed drugs demonstrate poor solubility in aqueous biological fluids [1]. Over long periods of time, inadequate solubility/dissolution rate and bioavailability have remained significant challenges in small drug molecule development and require more complex delivery systems. Among other approaches based on various physical and chemical modifications [2], manipulation of the solid form of drug compounds through the formation of solid dispersions (SDs) containing various additional substances designated as pharmaceutical excipients is of paramount importance. Literature surveys from the past decade have demonstrated a considerable expansion in the range of excipients and their combinations used in the production of SDs [3].

The list of the most used excipients contains substances with hydrotropic properties (for example, urea, nicotinamide, sugars, such as dextrose, sorbitol, maltose, xylitol, mannitol, lactose, etc.), biopolymers (polyethylene glycols, polyvinylpyrrolidone, or cellulose derivatives such as hydroxypropylmethylcellulose), surfactants (polyoxyethylene and polyoxypropylene copolymers, polyoxyethylene lauryl ethers, polyethylene glycol glycerides, and others), and cyclodextrins. The advent of multi-component SDs has significantly enhanced the possibilities of modifying the dissolution properties of poorly soluble APIs. Among these, the ternary cyclodextrin-polymer SDs have been thoroughly investigated [4], whereas the information on polymer-hydrotropic substances or cyclodextrin-hydrotropic substances is rather scarce [5,6]. The studies in the mixed solutions containing polymer/hydrotrope or cyclodextrin/hydrotrope demonstrated the advantageous synergistic action of both excipients on the solubility of poorly soluble hydrophobic drugs [7,8]. One can expect the same effect on the dissolution and/or permeation of SDs based on hydrotrope mixtures with other excipients. An additional component in a solid dispersion may serve not only as a solubilizing agent but also as a modifier of both drug release and diffusion through the membranes. Oral dosage forms with modified release are of great clinical significance and are characterized by the greatest diversity [9]. A number of studies focusing on the solubility-permeability relationship of APIs in SDs is steadily increasing [10,11,12,13]. The benefits of SDs, such as the minimization of permeability reduction or even an increase in permeation rate, are well-documented [14].

The aspects of stability are of special importance, particularly for such compounds as olanzapine crystallizing in various crystal forms. The formation of different polymorphic forms, hydrates, and solvates [15] complicates the accurate identification of the solid state and brings complexities to the drug formulation process. The stability of a drug in SDs is influenced by several factors, such as drug-excipient interactions, drug loading, manufacturing process, and storage conditions. The selection of an appropriate excipient is crucial for the design of stable drug compositions. The incorporation of a third component to form ternary solid dispersions (TSDs) can enhance stability by forming hydrogen bonds with the drug and/or other excipients, which helps to stabilize the amorphous form of the drug and prevents its recrystallization [16]. In vitro dissolution testing is typically carried out to evaluate the performance of newly formulated solid dispersions. However, these experiments are insufficient for predicting the intestinal absorption. For this purpose, methods that can simultaneously examine the dissolution and permeation of an API released from a formulation are often employed [17] using a side-by-side Franz diffusion cell and various artificial and biomimetic membranes [18].

Olanzapine (OLZ) is an antipsychotic drug belonging to the thienobenzodiazepines class, structurally similar to clozapine, which is used for the treatment of schizophrenia and bipolar affective disorder [19]. It belongs to Class II of the Biopharmaceutical Classification System (BCS) and exhibits inherently high permeability through biological membranes, but low aqueous solubility. OLZ was previously formulated into various solid dispersions with different excipients, resulting in improved aqueous solubility and dissolution rate compared to the pure drug [20,21,22]. But no studies on mixed solid dispersions based on OLZ could be found in the recent literature.

The aim of the present study was to prepare the two-component (1:1) solid dispersions of OLZ with sulfobutylether-β-cyclodextrin (SBE-β-CD), γ-aminobutyric acid (GABA), 6-aminocaproic acid (6ACA), choline bitartrate (ChB), and three-component solid dispersions OLZ/SBE-β-CD/GABA (1:0.25:0.75) and OLZ/SBE-β-CD/GABA (1:0.75:0.25) by ball milling technique and to examine and quantitatively characterize the dissolution and permeation rate of olanzapine upon its release from SDs. To achieve the maximum effect and in accordance with the recommendations reported in the literature [23], the dissolution and permeability experiments were conducted in a buffer medium at pH 7.4, in which the compound exhibited minimal solubility. The prepared SDs were thoroughly characterized by X-ray Phase analysis (PXRD), Fourier Transform Infrared (FTIR) and Raman spectroscopy, Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM) methods. The structures of OLZ and the excipients used are illustrated in Figure.

Mechanochemical Activation of Olanzapine in Mixed Solid Dispersions

Due to its polyanionic nature, SBE-β-CD binds particularly well to cationic, nitrogen-containing compounds [24,25]. SBE-β-CD is easily soluble in water (>500 mg·mL−1), has proven its worth as a safe solubilizer and stabilizer, is well tolerated in humans, and does not cause adverse effects on the kidneys or other organs following either oral or intravenous administration [26].

Optimal concentrations of excipients in dosage forms are selected to impart the necessary physicochemical and biopharmaceutical properties and to ensure the product’s quality, stability, safety, and efficacy. In many cases, this can be achieved by using a combination of several excipients rather than an excessive amount of a single one, thereby reducing their individual toxicity. In this study, we used ChB, GABA, and 6ACA as additional components of SDs alongside SBE-β-CD.

The bioactive compound GABA, a non-proteinogenic amino acid widely used in foodstuffs and pharmaceuticals, occurs widely in microorganisms, plants, and vertebrates. It is well known that GABA is the primary inhibitory neurotransmitter in the central nervous system, suppresses neurotransmission and tranquilization, manifests hypotensive/antihypertensive and diuretic effects, and also helps prevent sleeplessness and depression [27]. As a hydrotropic agent, GABA can enhance the solubility of certain compounds in water, similar to other hydrotropes. The dual role of GABA as both a neurotransmitter and a hydrotropic agent justifies its use in pharmaceuticals. It is a polar molecule, highly soluble in water, and capable of forming hydrogen bonds. GABA can modulate the permeability of intestinal epithelial cells, potentially influencing gut–brain communication [28].

The hydrophobic flexible structure of the ω-amino acid (6ACA) allows it to be used as a linker in various molecules and to improve the solubility of hydrophobic compounds due to its hydrotropic potential [29]. This compound is approved by the FDA for use in the treatment of acute bleeding caused by elevated fibrinolytic activity [30].

Short-chain choline carboxylates ChCm with m = 2, 4, 6 (including ChB) function as hydrotropes, solubilizing hydrophobic compounds in aqueous solution, whereas the longer-chain choline carboxylates ChCm with m = 8, 10 and choline oleate are capable of forming micelles [31].

The solubilizing effect of SBE-β-CD and ChB on OLZ was confirmed in our previous study [8]. Amino acids were utilized for their hydrotropic potential towards hydrophobic drug substances. Special attention was paid to GABA due to its antidepressant activity. Its combination with OLZ could serve as a basis for new pharmaceutical formulations.

Download the full article as PDF here Mechanochemical Activation of Olanzapine in Mixed Solid Dispersions

or continue reading here

Materials

Information on olanzapine and the chemicals used, including their main identification characteristics and sources, is provided in Table S1 (Supplementary Information). All chemicals were used as received. The structures of the investigated compounds are presented in Figure 1.

Volkova, T.; Simonova, O.; Perlovich, G. Mechanochemical Activation of Olanzapine in Mixed Solid Dispersions: Impact of Excipients on Release and Permeation Rates. Pharmaceutics 2026, 18, 411. https://doi.org/10.3390/pharmaceutics18040411