Pharmaceutical Nanotechnology
Formulation parameters of crystalline nanosuspensions on spray drying processing: A DoE approach

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Abstract

Nanocrystalline suspensions offer a promising approach to improve dissolution of BCS class II/IV compounds. Spray drying was utilized as a downstream process to improve the physical and chemical stability of dried nanocrystals. The effect of nanocrystalline suspension formulation variables on spray-drying processing was investigated. Naproxen and indomethacin nanocrystalline formulations were formulated with either Dowfax 2A1 (small molecule) or HPMC E15 (high molecular weight polymer) and spray drying was performed. A DoE approach was utilized to understand the effect of critical formulation variables, i.e. type of stabilizer, type of drug, ratio of drug-to-stabilizer and drug concentration. The powders were analyzed for particle size, moisture content, powder X-ray diffraction and dissolution. A dialysis sac adapter for USP apparatus II was developed which provided good discrimination between aggregated and non-aggregated formulations. Nanocrystal aggregation was dependent on the drug-to-stabilizer ratio. The glass transition temperature and the charge effect played a dominant role on spray-dried powder yield. Those formulations with low drug-to-excipient ratios were less aggregating and showed faster dissolution compared to those formulations with high drug-to-excipient ratios. All stable (less aggregated) formulations were subjected to accelerated storage stability testing. The Flory–Huggins interaction parameter (between drug and excipients) correlated with the spray-dried nanocrystal formulations stability.

Introduction

The popularity of nanosuspensions has increased over the past decade due to the escalation (approximately 40%) in the number of poorly soluble drug candidates coming out of drug discovery (Kipp, 2004, Lipinski et al., 2001, Lipinski, 2000, Lipinski, 2002, Gribbon and Sewing, 2005). The aqueous solubility of these drug molecules is in the order of a few nanograms to hundreds of nanograms per milliliter. These poorly soluble drug candidates must be formulated appropriately to enhance their dissolution rate and/or solubility and subsequently oral bioavailability. Apart from poor oral bioavailability, these drugs have several other disadvantages such as, fed versus fasted variation in bioavailability and the requirement of high doses to achieve therapeutic responses (Merisko-Liversidge and Liversidge, 2008). Several approaches have been utilized to formulate poorly soluble compounds such as solid dispersions, salt formation, prodrugs, screening for more soluble crystalline forms, preparation of nanosuspensions etc. The high exposed surface area of the nanocrystals increases the dissolution rate and hence oral bioavailability (Merisko-Liversidge and Liversidge, 2008, Merisko-Liversidge et al., 2003a, Merisko-Liversidge et al., 2003b). Apart from a bioavailability advantage, nanosuspension formulations have been shown to increase the chemical stability in some cases. For example, a paclitaxel aqueous nanosuspension formulation was stable up to 4 years (when stored at 4 °C) (Liversidge and Wei, 2003) compared to un-milled paclitaxel (80% degradation within 25 min) in water (Troester, 2004). The reason of nanosuspension stabilization was due to shielding or protection of the nano-sized crystalline paclitaxel by surface stabilizers.

There are several commercially available nano-particulate formulations and others are currently being evaluated in clinical trials (Kumar and Burgess, 2012). Nanosuspensions can be defined as suspensions of nano-sized drug particles suspended in stabilizer/s solutions. These solutions can be aqueous or non-aqueous and the typical size range for pharmaceutical nanosuspensions is 100–1000 nm. Nanosuspensions fall under the category of colloidal dispersions and can be prepared either via “top-down” or “bottom-up” approaches. Top-down approaches are based on milling or grinding of the drug particles in aqueous or mixtures of aqueous and non-aqueous solvents to achieve the required particle size. Bottom-up approaches are based on precipitation of the drug from solution (drug dissolved in organic solvent) using a solvent such as distilled water where the drug is insoluble. The size and stability of the nanosuspensions are dependent on the HLB of stabilizer and solubility of drug in stabilizer solutions, in bottom-up and top-down approaches, respectively (Verma et al., 2009). In addition, particles generated using these approaches may yield amorphous or partially crystalline material and their physical stability can be a critical issue (Muller et al., 2003).

Crystalline nanosuspensions have high surface area to volume ratios and thus (according to the Noyes–Whitney equation) (Noyes and Whitney, 1897) have faster dissolution rates and increased oral bioavailability.dCdt=DSVh(CSC)where dC/dt is the change in concentration, D is the diffusion coefficient, S is the surface area of the drug particle, h is the thickness of the diffusion layer, CS is the saturation solubility of the drug particle, C is the concentration of the drug in solution, and V as the total volume of the solution. In addition, according to the Kelvin equation (as shown below), saturation solubility (in terms of vapor pressure) of the drug is dependent on the drug particle size (which translates to curvature effects) (Simonelli et al., 1970). Theoretically, reduction in particle size will cause an increase in drug solubility. However, the predicted increase in saturation solubility for pharmaceutical nanosuspensions (approximately 300 nm) is marginal compared to un-milled particles.SS0=exp4γVdRTwhere S is the solubility, S0 the solubility of bulk material, R the gas constant, V the molar volume, T the temperature, d the diameter of particle and γ the surface free energy.

Nanosuspensions being a liquid dosage form are physically and chemically unstable. Drug particles in aqueous environment can undergo chemical degradation such as hydrolysis. Nanosuspension formulations are known to undergo Ostwald's ripening as well as phase separation or precipitation. To prevent chemical as well as physical instability, drying of nanosuspensions is employed. Freeze and spray-drying processes are typically used to dry nanosuspensions (Van Eerdenbrugh et al., 2008a, Chaubal and Popescu, 2008). The advantages of dried formulations are improvement in chemical and physical stability and processibility into tablets or capsules. The drying process itself can lead to issues such as, aggregation on re-dispersion of dried powders, drug degradation and delayed dissolution rates. There are several reports which deal with spray and/or freeze-drying of nanosuspensions (Van Eerdenbrugh et al., 2008a, Van Eerdenbrugh et al., 2008b, Van Eerdenbrugh et al., 2008c, Chaubal and Popescu, 2008, Lee, 2003, Cerdeira et al., 2013) but none of these explain the importance of the process and formulations parameters during nanosuspension drying. Our previous research has focused on the effect of spray drying process parameters on the critical quality attributes (CQA) of nanosuspensions. This current study highlights the importance of critical nanosuspension formulation variables involved during spray drying processing.

We have utilized a design of experiment (DoE) approach to classify and quantify all the critical formulation variables involved during spray drying of nanosuspensions. We have chosen two poorly soluble biopharmaceutical classification system (BCS) class II model drugs (i.e. indomethacin and naproxen). Dowfax 2A1 (small molecule ionic surfactant) and HPMC E15 (non-ionic polymer) were used for the stabilization of liquid nanosuspension formulations. Based on our preliminary study, we have selected four critical parameters, i.e. type of drug, type of excipient, concentration of drug and ratio of drug-to-stabilizer for this study. A full factorial design was utilized with two qualitative and two quantitative factors. The CQAs were particle size, yield, moisture content, polymorphic form, dissolution and stability of the spray-dried nanocrystal powders. ANOVA was utilized to analyze the effect of critical formulation parameters on the quality attributes of spray-dried powders. To the best of our knowledge, no exhaustive DoE study has been conducted that describes the effect of nanosuspension formulation variables on the quality of the spray-dried powder.

At present, United States Pharmacopeia (USP) does not have any official or standard method(s) for in vitro release testing of colloidal/disperse dosage forms. Currently used techniques can be broadly divided into two categories: (1) sample and separation methods and (2) membrane diffusion methods (such as dialysis sac, reverse dialysis sac, micro-dialysis, and Franz cells). These techniques are required to isolate the dosage form from the release media for analytical purposes. However, these existing methods do not use official USP dissolution/release apparatus. Accordingly, the methodology changes with operator and laboratory, introducing undesirable variations. Therefore, results from different sources are usually not comparable. The present study aims to address this problem by designing and developing a dialysis adapter to be used in conjunction with compendial USP dissolution apparatus II.

Section snippets

Materials

Indomethacin USP, γ polymorph, was purchased from PCCA (Houston, TX). Naproxen was purchased from Gallipot. Dowfax 2A1 (alkyldiphenyloxide disulfonate) and HPMC E15 (premium LV) were generously gifted by Dow Chemical Company (Midland, MI). HPLC grade acetonitrile (ACROS chemicals) was purchased from Fisher scientific (Waltham, MA). Hermetic pans and lids were purchased from TA instruments (New Castle, DE) and Float-A-Lyzer dialysis sacs (MWCO 1000 kDa) were purchased from Spectrum labs (Spectrum

Effect of formulation variables on nanocrystal aggregation during spray drying

As shown in Table 1, all spray-dried formulations showed aggregation. One critical variable was identified as a significant parameter for nanocrystals aggregation, i.e. drug-to-stabilizer ratio. All other variables were not significant as shown in Table 2. It was noted that formulations containing high concentrations of stabilizers (i.e. either Dowfax 2A1 or HPMC E15) were less aggregated compared to formulations with lower stabilizer concentrations (Fig. 4). Both small molecule (Dowfax 2A1)

Conclusions

This is the first report, which deals with the effect of formulation variables on the critical quality attributes of spray-dried nanocrystal powder. The aggregation tendency of spray-dried nanocrystal powders showed a dependency on the drug-to-stabilizer ratio. The formulations containing higher concentrations of excipients showed less aggregation compared to formulations containing lower concentrations of excipients. We have developed a dialysis sac adapter for USP apparatus II. This adapter

Acknowledgments

We gratefully acknowledge financial support from Dane O. Kildsig Center of Pharmaceutical Processing and Research. We are thankful to Mr. Jack Gromek at the Institute of Material Science, University of Connecticut for his assistance with X-ray diffraction instrument and Dr. Michael Pikal for use of the DSC (TA Q1000) instrument.

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    Current address: FDA/CDER, Division of Product Quality Research, Silver Spring, MD 20993, USA.

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