Influence of Drying Methods on Redispersibility and Dissolution of Canagliflozin Nanocrystals: A Comparative Approach

Abstract

Background/Objectives: Canagliflozin (CFZ) is the first sodium glucose co-transporter 2 (SGLT-2) inhibitor and is characterized by poor water solubility and permeability, resulting in low oral bioavailability. In this study, a CFZ nanosuspension (CFZ-NS) was converted into a solid form to improve the physical stability of CFZ nanocrystals (CFZ-NCs) and to enable formulation as a tablet dosage form.

Methods: To achieve adequate redispersibility of dried CFZ-NCs, fluid bed granulation and spray-drying methods were employed, and the effects of critical process parameters were investigated. The stability of spray-dried nanocrystal tablets (NCs-SD-TAB) was evaluated over a three-month period under storage conditions of 25 ± 2 °C with 60 ± 5% relative humidity (RH) and 40 ± 2 °C with 75 ± 5% RH.

Results: The highest redispersibility index (94%) was obtained using the spray-drying method. Tablets prepared with spray-dried NCs-SD-TAB exhibited a significantly higher in vitro dissolution rate under non-sink conditions compared with control tablets prepared using unprocessed CFZ with the same excipients, as well as the marketed product. NCs-SD-TAB showed an approximately three-fold increase in drug release at 15 min in 0.1 N HCl, with a pH 4.5 acetate buffer and pH 6.8 phosphate buffer, which simulate gastrointestinal pH conditions, relative to the marketed product.

Conclusions: Overall, these results indicate that nanocrystal technology represents a promising approach for CFZ as an improved oral drug-delivery system, primarily due to its solubility enhancement capabilities.

Introduction

The International Diabetes Federation estimates that 537 million people aged 20–79 years had diabetes worldwide in 2021, and this figure may rise to 783 million by 2045 [1]. Although Diabetes Mellitus (DM) has been recognized as a clinical problem for more than two centuries, its treatment and management remain challenging [2], and the disease is considered the sixth leading cause of mortality worldwide [3]. In recent years, nanocrystal technology has attracted increasing interest in anti-diabetic drug delivery due to its potential to enhance dissolution-limited oral absorption. While many studies report improved in vitro dissolution rates, achieving consistent bioavailability and therapeutic benefits in humans depends on the specific drug and formulation [4].

Nanosuspension-based systems can also enable modulation of drug release behavior, potentially yielding more stable plasma drug levels and improved glycemic control, which may reduce the risk of acute hypoglycemia and long-term diabetic complications [5].

Canagliflozin (CFZ), the first member of the SGLT2 inhibitors, lowers plasma glucose levels by increasing urinary glucose excretion in patients with type 2 DM, causing mild osmotic diuresis and a net calorie loss [6]. Beyond lowering glucose, they reduce glycated hemoglobin (HbA1c) levels and are associated with improved renal outcomes and reduced cardiovascular events through multiple mechanisms, including renoprotection, the attenuation of glomerular hyperfiltration and albuminuria, enhanced sodium excretion, and a concomitant reduction in blood pressure [7,8]. On the other hand, CFZ is practically insoluble in aqueous media over a wide pH range (pH 1.1–12.9) [9], and its absolute oral bioavailability is approximately 65%, indicating poor to moderate permeability.

Accordingly, the applicants Mitsubishi Tanabe Pharma and Johnson and Johnson have classified CFZ as a Biopharmaceutical Classification System (BCS) Class IV drug [10]. Low oral bioavailability therefore remains a major limitation for certain contemporary diabetes treatments [11]. It is well established that the oral absorption of active pharmaceutical ingredients with low water solubility can be highly variable, potentially leading to inconsistent systemic exposure. However, many anti-diabetic drugs that are currently available on the market are adequately soluble and can be formulated successfully without the need for specialized solubilization strategies. In contrast, for poorly water-soluble anti-diabetic compounds, dissolution-limited absorption can be a key factor affecting oral bioavailability and therapeutic performance [12].

Nanocrystal (NC) technology is one of the most widely explored approaches among nanotechnology-based drug delivery systems, with more than 20 NC drug products currently available on the pharmaceutical market [13]. The widespread adoption of NCs by both the pharmaceutical industry and researchers is primarily attributed to their submicron particle size (<1000 nm). They are especially commonly produced by the wet grinding technique, yielding particles in the range of 200–400 nm dispersed in aqueous media with stabilizers; such systems are therefore often referred to as nanosuspensions. By definition, nanocrystal systems are carrier-free formulations composed of the active pharmaceutical ingredient stabilized by small amounts of surface-active agents, in contrast to most nanocarrier-based formulations, which incorporate substantial amounts of excipients. This characteristic enables a theoretical drug loading of up to 100% while also allowing a simplified formulation design and greater flexibility for scaling up [14].

Moreover, owing to their carrier-free nature and reduced dependence on excipients, nanocrystals generally require fewer stabilizers and may exhibit lower toxicity than carrier-based systems such as nanoparticles and liposomes [15]. Particle size reduction increases the surface area and surface free energy, thereby enhancing saturation solubility [16], dissolution rate [17], enhanced transport across the intestinal membrane [16,18], and ultimately oral bioavailability [19,20]. Nevertheless, drug nanosuspensions face significant challenges related to their physical stability. As colloidal dispersions, they exhibit a strong tendency to aggregate in order to minimize their surface energy and may undergo time-dependent, solution-mediated recrystallization phenomena whereby material redistribution between particles can occur [21]. Addressing these physical stability issues is therefore essential for the successful development of a nanocrystal-based drug delivery system.

Considering the thermodynamic instability of nanosuspensions, the conversion of drug nanosuspensions into a solid state by the drying process represents a valuable approach to achieving optimal stability [22]. Although the drying process is a critical step in transforming nanosuspensions into solid forms, it may induce particle aggregation or particle growth due to thermal stress and the removal of the liquid phase [23]. Therefore, a thorough understanding of the drying process and critical parameters that strongly influence the redispersibility of dried powders is essential, along with the careful selection of an appropriate drying method [23,24]. In the drying process, various techniques are employed, including freeze drying, spray-drying, vacuum drying, pelletisation, granulation/coating in a fluidized bed dryer, drum drying, and electro-spraying [25]. In this study, fluidized bed granulation and spray-drying were selected, as the former is widely preferred by the pharmaceutical industry, and the latter is extensively used for the drying of nanosuspensions.

The drying of nanosuspensions not only ensures optimum stability but also enables their conversion into solid dosage forms, such as capsules and tablets, and is suitable for oral administration [26]. In the present study, CFZ-NS optimized in our previous study [27] was dried using a suitable method and subsequently transformed into a tablet dosage form via the direct compression (DC) method. DC is a preferred technique as it involves a minimum number of processing steps, eliminating the need for intermediate procedures such as granulation and thereby reducing both production costs and time [28]. However, in order to produce tablets with adequate mechanical strength and content uniformity, both active ingredients and excipients must exhibit suitable flowability, compressibility, compactibility, and limited elastic recovery.

This study mainly focuses on the conversion of CFZ-NS into a solid form with desirable redispersibility. To achieve this objective, top spray granulation and spray-drying methods were employed, and the effects of key process parameters on particle size and in vitro drug release behavior were systematically investigated. To facilitate practical application, the dried CFZ-NCs were subsequently formulated into a tablet dosage form using excipients suitable for DC. The resulting tablets were evaluated for weight variation, content uniformity, breaking strength, friability, in vitro disintegration time, and in vitro drug release under non-sink conditions. In addition, stability studies were conducted for 3 months under controlled conditions of 25 ± 2 °C with 60 ± 5% RH and 40 ± 2 °C with 75 ± 5% RH. Overall, this work aims to develop nanocrystal-based tablet formulations with enhanced dissolution performance, which may ultimately improve patient compliance.

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3. Materials and Methods

3.1. Materials

The purchase of canagliflozin (hemi-hydrate) (d90: 18.119 µm) was made from Fuxin Long Rui Pharmaceutical Co., Ltd. (Fuxin, China). D-Mannitol with different particle size grades (Pearlitol® 50C, Pearlitol® 160C) and alpha-lactose monohydrate grades (Granulac® 200 and FlowLac® 100) was supplied by Roquette, Geneva, IL, USA, and Meggle, Wasserburg am Inn, Germany, respectively. Magnesium stearate (Parteck® LUB MST) and silicified microcrystalline cellulose (Prosolv® SMCC 90) were obtained from Merck, Darmstadt, Germany, and JRS Pharma, Rosenberg, Germany, respectively. Acetonitrile (HPLC grade) and o-phosphoric acid (85%) were obtained from Merck Millipore, Darmstadt, Germany, and ISOLAB, Eschau, Germany, respectively, and were utilized as components of the mobile phase for the HPLC analysis.

3.2. Preparation of Optimized CFZ-NS

The CFZ-NS was optimized in our previous study [27]. Briefly, 1.30% hydroxymethyl propyl cellulose (HPMC-E15), 0.50% Poloxamer 407 (P407), 0.08% Tween 80 (T80), and 0.02% Sodium lauryl sulfate (SLS) were dissolved in deionized water, after which 4.25% CFZ was added. The resulting mixture was subjected to a wet milling process using a Dynomill® (Willy A. Bachofen AG, Muttenz, Switzerland) for 1 h with 0.35 L zirconium beads (0.3 mm). HPMC is a hydrophilic polymer, while P407 and T80 are non-ionic amphiphilic surfactants that provide steric stabilization by forming a mechanical barrier between nanocrystalline drug particles. In contrast, SLS is an anionic surfactant that imparts an electrostatic charge to the particle surface. The combination of steric and electrostatic stabilisation mechanisms is commonly employed to obtain nanosuspensions and nanocrystals with enhanced physical stability and reduced particle size; this approach is referred to as electrosteric stabilization [27].

Pirincci Tok, Y.; Demiralp, B.; Güngör, S.; Sarikaya, A.O.; Aldeniz, E.E.; Dude, U.K.; Ozsoy, Y. Influence of Drying Methods on Redispersibility and Dissolution of Canagliflozin Nanocrystals: A Comparative Approach. Pharmaceuticals 2026, 19, 240. https://doi.org/10.3390/ph19020240