Impact of Surfactants on the Crystallization of Aqueous Suspensions

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Impact of Surfactants on the Crystallization of Aqueous Suspensions of Celecoxib Amorphous Solid Dispersion Spray Dried Particles Jie Chen, James D. Ormes, John D. Higgins, and Lynne S. Taylor Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp5006245 • Publication Date (Web): 08 Jan 2015 Downloaded from http://pubs.acs.org on January 16, 2015

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Molecular Pharmaceutics

Impact of Surfactants on the Crystallization of Aqueous Suspensions of Celecoxib Amorphous Solid Dispersion Spray Dried Particles

Jie Chen1, James D. Ormes2, John D. Higgins3 and Lynne S. Taylor1*

1

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University,

West Lafayette, IN, 47907, USA 2 Basic Pharmaceutical Sciences, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, 07065, USA 3

Basic Pharmaceutical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point,

PA 19486, USA

Corresponding Author *(L.S.T.) Address: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, USA. Tel: +1-765496-6614; Fax: +1-765-494-6545; e-mail: [email protected].

ACS Paragon Plus Environment


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ABSTRACT Amorphous solid dispersions are frequently prepared by spray drying. It is important that the resultant spray dried particles do not crystallize during formulation, storage and upon administration. The goal of the current study was to evaluate the impact of surfactants on the crystallization of celecoxib amorphous solid dispersions (ASD), suspended in aqueous media. Solid dispersions of celecoxib with hydroxypropylmethylcellulose acetate succinate were manufactured by spray drying and aqueous suspensions were prepared by adding the particles to acidified media containing various surfactants. Nucleation induction times were evaluated for celecoxib in the presence and absence of surfactants. The impact of the surfactants on drug and polymer leaching from the solid dispersion particles was also evaluated. Sodium dodecyl sulfate and Polysorbate 80 were found to promote crystallization from the ASD suspensions while other surfactants including sodium taurocholate and Triton X 100 were found to inhibit crystallization. The promotion or inhibition of crystallization was found to be related to the impact of the surfactant on the nucleation behavior of celecoxib, as well as the tendency to promote leaching of the drug from the ASD particle into the suspending medium. It was concluded that surfactant choice is critical to avoid failure of amorphous solid dispersions through crystallization of the drug. Keywords: spray dried particles; crystallization; surfactants; polymers


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INTRODUCTION Formulation of poorly water soluble drugs to achieve adequate plasma exposure levels is currently a major challenge. This is particularly true in early phase development during toxicity testing where very high exposure levels are required in order to evaluate the safety of the new molecular entity. Historically, a variety of solubilization techniques have been used to enhance drug solubility and/or dissolution rate, including pH adjustment1, solubilization in surfactant micelles and lipids2, cosolvents3, solid dispersions4, and nanocrystals5. Nanocrystals achieve dissolution rate enhancement by a reduction in particle size. Solid dispersions, on the other hand, utilize the high energy amorphous solid form whose theoretical solubility is usually several times higher than that of the crystalline form6. However due to its thermodynamic instability, amorphous forms tend to transform to crystals and lose their solubility enhancement. This process is typically accelerated upon exposure to heat, moisture and solvents7. Therefore, stabilizing additives that impede crystallization are mixed with the drug substance to make amorphous solid dispersions (ASD). Common methods used to prepare ASDs include quench cooling from the melt, fast solvent evaporation, melt extrusion, spray drying and electrospinning/spraying8. In toxicology testing, solid dispersion particles are usually formulated as suspensions and dosed to animals by oral gavage. By using a polymer with pH-dependent solubility in the ASD formulation, a suspension can be maintained by adjusting the pH of the liquid medium to acidic conditions where the polymer is largely insoluble, hindering the dissolution of the solid dispersion particles. For this approach to be useful, crystallization must be prevented over the lifetime of the suspension. This is also true for commercial ASDs formulated with enteric polymers which should not undergo crystallization when present in the stomach before they start



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dissolving in the higher pH environment of the small intestine. Suspension formulations are further complicated by the presence of various excipients, added to the liquid medium in order to achieve a stable and functional suspension. Polymers are used to increase the viscosity of the liquid medium, keeping the particles suspended, while surfactants are often added to improve both the wetting of the solid dispersion particles and the rheological properties of the suspension. Anti-nucleation agents such as polymers can also be added to retard drug crystallization9, the risk of which is greatly increased upon contact of the formulation with water. Currently, formulation of ASD suspensions is largely empirical with methods such as high throughput screening being used to screen for a viable suspension formulation for a given solid dispersion. Because the liquid medium is a complex multi-component system, the understanding of how each individual additive and their interactions influence the stability of the suspension is limited. Most studies to date have focused on the impact of polymeric additives as crystallization (both nucleation and crystal growth) inhibitors10, while the influence of surfactants on crystallization is often neglected. However, in the context of crystallization and crystal engineering, it has been demonstrated that surfactants can enhance nucleation, accelerate solution-mediated polymorph transformation, as well as influence crystal growth 11. Therefore, attention should be paid to the impact that surfactants have on the stability of amorphous suspensions. In this work, we systematically studied the impact of five commonly used surfactants on the stability of ASD suspensions of celecoxib formulated with hydroxypropyl methylcellulose acetate succinate (HMPCAS). Surfactants studied were: sodium dodecyl sulfate (SDS), sodium taurocholate (STC), Polysorbate 80, Poloxamer 188, and Triton X100. SDS is a commonly used anionic surfactant with a charged hydrophilic head and a linear C12 tail. STC is also an anionic surfactant. It belongs to the bile salt family and has a charged hydrophilic head and a rigid


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steroid ring system that exhibits facial polarity (hydrophilic and hydrophobic planes). Polysorbate 80 is a neutral surfactant which has polyoxyethylene groups as the hydrophilic portion and a chain-like C20 tail. Poloxamer188 is an EO-PO-EO (EO, ethylene oxide; PO, propylene oxide) block copolymer. The EO groups are hydrophilic while the PO groups are hydrophobic. Triton X100 is a nonionic surfactant which has a polyoxyethylene group as the hydrophilic head (similar to Polysorbate 80 and Poloxamer 188) but a bulky aromatic hydrocarbon hydrophobic group. The structures of the drug, polymer and surfactants used in this work are shown in Figure 1. The objectives of this study were (1) to determine if crystallization of celecoxib occurs in/at the surface of the suspended ASD particles or from the solution phase following leaching of the drug; (2) to evaluate the impact of surfactants on the crystallization of celecoxib by studying the surfactant impact on celecoxib crystal nucleation and drug leaching; (3) to gain insight into structure-property relationships between surfactant and its impact on suspension stability.

Celecoxib

Sodium dodecyl sulfate (SDS)

HMPCAS

Sodium taurocholate (STC)



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Triton X100

Polysorbate 80

Poloxamer 188 Figure 1. Molecular structures of celecoxib, HPMCAS and surfactants.

MATERIALS AND METHODS MATERIALS Celecoxib was obtained from Matrix Scientific (Columbia, SC). HPMCAS (LF grade) was obtained from Shin-Etsu (Japan). Sodium taurocholate hydrate, STC ( ≥97.0%, Sigma, St. Louis, MO), sodium dodecyl sulfate, SDS (≥99.0%, Sigma, St. Louis, MO), Polysorbate 80, Poloxamer188, TritonTM X100 (laboratory grade, Sigma, St. Louis, MO) were used as received. The initial aqueous medium was prepared at room temperature by adding 0.5 N HCl aqueous solution (Sigma, St. Louis, MO) to de-ionized water (Milli-Q, 18.2 mΩ) untill the pH value of solution reached 3. All solutions containing surfactant were prepared by adding the desired amount of surfactant to the pH adjusted solution. METHODS


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Preparation and characterization of solid dispersion particles Solid dispersions of celecoxib in HPMCAS at a drug loading of 33.3 w/w% (COX/HPMCAS DL 33.3 w/w%) were prepared by spray drying. Celecoxib and HPMCAS were dissolved in acetone at 20 mg/mL and 40 mg/mL, respectively. The mixture was alternately stirred on a magnetic stir plate and submersed into a Branson Ultra-Sonicator until all components had dissolved. Materials were spray dried using a ProCepT Microspray Dryer with a bifluid nozzle. Key operation parameters include nozzle size (0.8 mm), spray rate (6 mL/min), inlet temperature (85 +/- 5 °C), outlet drying temperature (55 +/- 5 °C) and atomization air flow (4 L/min). The spray dried dispersion was collected using small cyclone separation. Solids were stored in a vacuum oven overnight at room temperature for secondary drying. The amorphous character of solid dispersion particles was verified using polarized microscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The cross-polarized optical microscope used was a Nikon Eclipse E600 Pol microscope, with NIS-Elements version 2.3 software package (Nikon Co., Tokyo, Japan). The diffractometer used was a Shimadzu XRD 6000 diffractometer (Shimadzu Scientific Instruments, Columbia, MD). The DSC analysis was performed using a TA Instruments Q2000 instrument (TA Instruments, New Castle, DE) attached to a refrigerated cooling accessory (RCS) (TA Instruments, New Castle, DE). The thermogram of the solid dispersion was obtained by heating the sample from 25 °C to 170°C at a rate of 10 °C/min.

Determination of celecoxib solubility and surfactant critical micelle concentration (CMC). The solubility of crystalline celecoxib (Form III) in different liquid media was determined by adding an excess amount of the drug to 15 mL of solvent. The mixture was stirred and allowed to



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equilibrate for 48 hours at 25 °C and then centrifuged. Ultracentrifugation was performed at 40,000 rpm in an Optima L-100 XP ultracentrifuge equipped with a Swinging-Bucket Rotor SW 41 Ti (Beckman Coulter, Inc., Brea, CA). The supernatant was diluted using methanol prior to concentration determination using an Agilent 1260/1290 Infinity Series HPLC system (Agilent Technologies, Santa Clara, CA). The chromatographic separation was performed with a ZORBAX Eclipse Plus C18 analytical column (250 mm × 4.6 mm i.d., 5 µm) (Agilent Technologies, Santa Clara, CA). The mobile phase was a mixture of water (25%) and methanol (75%), the flow rate was 1.25 mL/min, and the injection volume was 20 µL. The eluent was monitored at 250 nm using an ultraviolet detector 12. Because the presence of drug molecules can change the critical micelle concentration of a surfactant, the CMC of all five surfactants in the presence of celecoxib was determined by measuring the solubility of celecoxib in solutions containing varying amounts of surfactant. Below and above the CMC, the drug solubility increased linearly with the surfactant concentration, but at a different rate. CMC was taken as the surfactant concentration where this rate change occurred, i.e. where the slopes intersected. Following the determination of the CMC, a surfactant concentration 11% above its CMC was selected for each surfactant in subsequent mechanistic studies of celecoxib nucleation induction times and drug leaching. One concentration below CMC was also studied for SDS and STC, respectively, in the nucleation induction time study to study the influence of the presence and absence of micelles. Nucleation induction time measurements. The impact of surfactants on the crystallization tendency of celecoxib from the solution phase was evaluated by measuring the nucleation induction time using the method described by


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Ilevbare et al. 9a To compensate for the difference in the solubilizing abilities of the various surfactants, all nucleation induction time studies were performed using a constant initial supersaturation of 5 at 25 °C which is equivalent to an initial concentration equal to five times the equilibrium concentration of celecoxib Form III measured in the presence of the surfactant. Using a constant supersaturation for all induction time measurements ensured that the driving force for nucleation stayed constant between the different systems. Supersaturation was generated by titrating an appropriate amount of celecoxib stock solution in methanol (usually around 100 µL) to 50 mL solution while stirred using a cross-shaped magnetic stirrer at 300 rpm. The onset of nucleation was determined from the increase in intensity of light scattered (extinction) from the drug solutions upon evolution of particles. Light scattering was detected by monitoring the extinction at 350 nm using a SI Photonics UV/vis spectrometer (Tuscon, Arizona), fiber optically coupled with a dip probe (path-length 10 mm). Each experiment was repeated at least three times to calculate the average induction time. Amorphous suspension stability. Amorphous suspensions of celecoxib were prepared by adding 100 mg of spray dried COX/HPMCAS (DL 33.3 w/w%) particles to 10 mL liquid medium in a 20 mL scintillation vial to achieve a solids loading of 10 mg/mL. All suspensions were kept at 25 °C and stirred at 150 rpm with magnetic stirring. Six different liquid media were tested, namely HCl solution (pH=3) without any surfactant and with five different surfactants. All surfactant concentrations were 11% above CMC. A drop of the suspension was placed on a microscope slide and visually inspected under a polarized light microscope at time intervals of 0.5, 1, 2, 4, 6, 24 and 48 hours. The stability of the amorphous suspension was assessed based on the presence or absence of crystalline birefringent particles.



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Drug and polymer leaching The kinetics of celecoxib and polymer leaching from the ASD particles into the liquid medium was monitored by measuring the drug and polymer concentration in the solution phase at different time intervals up to 24 or 48 hours. For each time point, a 10 mL volume of suspension with a solids loading of 10 mg/mL was filtered using a syringe filter with a 0.45 µm pore size nylon membrane. The filtrate was diluted using methanol prior to determining the celecoxib concentration using the HPLC method described above. To determine the concentration of polymer, a colorimetry method was used13. Phenol (89%, 0.05 mL, Sigma, St. Louis, MO) and sulfuric acid (>51%, 5 mL, Macron, Center Valley, PA) were added to 2 mL of the filtrate. The solution was shaken and allowed to stand for 1 hour and a yellow-orange color subsequently developed. The absorbance was determined at 490 nm using a UV/Vis spectrometer (Cary Bio 50 UV/Visible Spectrophotometer, Varian Analytical Instruments (Santa Clara, CA)). A calibration curve was prepared using known polymer concentrations (2–20 mg/mL) in pH=3 HCl solution.

RESULTS Solid state properties of spray dried particles. The solid dispersion of COX/HPMCAS (DL 33.3 w/w%) was amorphous following spray drying whereby no birefringence was observed under polarized light (Figure 2a). Based on the DSC thermogram, the solid dispersion had a single glass transition event at 61 °C (midpoint) and no thermal events around 165 °C which is the melting temperature of crystalline celecoxib form III.


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The absence of sharp peaks in the XRPD pattern confirms the amorphous nature of the COX/HPMCAS (DL 33.3 w/w%) solid dispersion prepared using the spray-dry method. 0.2

Heat Flow (W/g)

0.0

51.64°C 60.60°C(I) 0.3293J/(g°C)

-0.2

61.19°C

-0.4

-0.6

0

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(a)

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COX-HPMCAS (DL 33.3 w/w%)

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crystalline celecoxib Form III

500 Intensity

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400 300 200 100 0 0

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(c) Figure 2. Characterization of COX/HPMCAS (DL 33.3 w/w%) solid dispersion particles. (a) Microscopic image obtained using a 20X objective and cross polarized light; (b) DSC thermogram; (c) XRPD patterns of COX/HPMCAS (DL 33.3 w/w%) solid dispersion (solid line) and crystalline celecoxib samples (dashed line).

Solubility of celecoxib and surfactant critical micelle concentration (CMC).



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The CMC’s of SDS, STC, Polysorbate 80, Poloxamer 188 and Triton X100 in pH 3 HCl solution in the presence of celecoxib at its saturation solubility were 0.23%, 0.69%, 0.0058%, 0.16% and 0.022% (w/w) , respectively. Therefore the concentrations of surfactants (11% above CMC) used in the nucleation induction time and the drug leaching studies were 0.25%, 0.75%, 0.0064%, 0.17% and 0.025%, respectively. The corresponding equilibrium solubility of celecoxib in the presence of the surfactants at these concentrations (25 °C) was 14.5, 5.8, 2.0, 1.4 and 3.7 µg/mL, respectively. For the lower surfactant concentrations (i.e. below CMC, 0.175% and 0.4% for SDS and STC respectively); the corresponding equilibrium solubilities of celecoxib are 1.7 and 2.4 µg/mL. The solubility of celecoxib in pure aqueous HCl solution (pH = 3) was 1.1 µg/mL. It is obvious that the presence of surfactant enhances the drug solubility. The solubility of celecoxib in surfactant containing solutions at other concentrations can be found in the supporting information (Tables S1-5 and Figures S1-5). Nucleation induction time. The goal of the nucleation induction time measurements was to evaluate the impact of surfactants on the crystallization tendency of the drug in the bulk solution, to simulate the situation where drug has leached from the ASD particles. After addition of the stock solution of celecoxib to 50 mL buffer solutions, the initial solution is supersaturated and has no particles, and hence the intensity of scattered light (extinction monitored at 350 nm) is close to zero. When nucleation occurs, the number of particles in the system increases, as does the intensity of scattered light. A typical time evolution of extinction as a function of time at 350 nm is shown in Figure 3, whereby the nucleation induction time was determined by drawing regression lines through the two distinct linear regions. The intersection point of the regression lines for these two regions was taken as the nucleation induction time, τ. The impact of the different surfactants


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on the induction time of celecoxib nucleating from solution is shown in Figure 4. Using the nucleation induction time from the HCl solution with no surfactant as the reference, it can be seen that Polysorbate 80, Poloxamer 188 and SDS all accelerated the nucleation of celecoxib, with the enhancing effect following the order of Polysorbate 80 > Poloxamer 188 > SDS. In contrast, Triton X100 and STC, both inhibited nucleation. The nucleation induction time experiments with STC were only monitored for 16 hours and no sudden increase in the intensity of light scattered was observed throughout the entire course of the experiment. Therefore the nucleation induction time for this system, although not accurately determined, appears to be longer than 960 minutes. Interestingly, the enhancing effect of SDS and the inhibitory effect of STC occurred even for surfactant concentrations below the CMC. Celecoxib crystals formed during the nucleation induction time experiments were collected at the end of the experiment and visualized using microscopy. All crystals exhibit a morphology of thin needles consistent with the formation of the Form III polymorph.

Figure 3. Extinction monitored at 350 nm as a function of time for celecoxib nucleating from an aqueous HCl solution (pH = 3) containing 0.25% SDS.



273

>960

400 350 Induction time (min)

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Figure 4. Nucleation induction times for celecoxib crystallizing from pH 3 solution containing different surfactants at 25 °C and at a supersaturation of 5.

Amorphous suspension stability The stability of amorphous spray dried particles suspended in different liquid media to crystallization is summarized in Table 1. SDS and Polysorbate 80 undermine the stability of the amorphous suspension whereby needle-like crystals of celecoxib were observed floating in the bulk of the liquid medium at 0.5 hour for SDS and 1 hour for Polysorbate 80 (Figure 5a and b). In contrast, in the absence of surfactants, no crystals were observed for up to 48 hours (Figure 5c). After 24 hours, samples of the suspensions were filtered, dried and analyzed using XRPD. The XRPD patterns suggest that they are mixtures of celecoxib crystals (Form III) and the residual amorphous solid dispersion. The recrystallized needle-like celecoxib crystals have their


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needle direction aligned with the c-axis (Figure 6). The amorphous suspensions with Poloxamer 188, Triton X100, or STC are stable over a period of 48 hours with no crystalline particles observed (Figure 5 d-f). Table 1. Physical Stability of amorphous suspensions in the presence and absence of various surfactants as a function of time. ‘X’ and ‘-’ indicate the presence and absence of crystalline particles, respectively. 0.5 hr

1 hr

2 hr

4 hr

6 hr

24 hr

48 hr

SDS 0.25%

X

X

X

X

X

X

X

Polysorbate 80 0.0064%

-

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X

X

X

X

X

HCl solution (pH = 3)

-

-

-

-

-

-

-

Poloxamer 188 0.17%

-

-

-

-

-

-

-

Triton X100 0.025%

-

-

-

-

-

-

-

STC 0.75%

-

-

-

-

-

-

-

(a) SDS 0.5 h

(b) Polysorbate 80 1 h



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(c) HCl pH 3 48 h

(d) Poloxamer 188 48 h

(e) Triton X100 48 h

(f) STC 48 h

Figure 5. Microscopic images of COX/HPMCAS (DL 33.3 w/w%) particles after suspension in different aqueous media.


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Figure 6. XRPD patterns of COX/HPMCAS (DL 33.3 w/w%) slurried in 0.25% SDS buffer at 25 °C (red) and reference celecoxib Form III crystals (blue).

Drug and polymer leaching When a suspension is prepared by adding spray dried COX/HPMCAS solid dispersion particles to an aqueous medium, both the drug and the polymer can leach from the solid phase into the solution phase. Drug leaching is a complex process because celecoxib in the ASD is present as the amorphous form. Thus a supersaturated solution can be generated by drug leaching, followed by a subsequent drop in concentration if crystallization of the drug occurs. In contrast, the polymer will dissolve to a constant value according to its solubility in the medium. The concentrations of celecoxib in the solution phase as a function of time following suspension of the ASD particles in media containing different surfactants are shown in Figure 7. All concentrations were normalized to the equilibrium solubility of celecoxib in the corresponding solution and thus the extent of supersaturation achieved is shown. Here it is assumed that the presence of a small amount of HPMCAS in the solution resulting from its leaching from the solid dispersion particles does not change the equilibrium solubility of celecoxib to a large extent. The greatest extent of celecoxib leaching was observed in the SDS solution. The drug concentration rapidly obtained a value of around 107 µg/mL in a 10 minute period, corresponding to a supersaturation level of 7.4. Subsequently, a rapid decrease in concentration to a supersaturation level of 3.2 occurred due to the crystallization of drug followed by a slight increase over the next 23 hours. The extent of drug leaching from HCl pH 3 solution, and solutions containing Polysorbate 80, STC and Poloxamer 188 was lower, with the maximum supersaturation being reached in in the first six hours with values ranging from 3.4 to 5.4. Similar to the SDS



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containing solution, a drop in supersaturation from 3.4 to 1.1 was observed in the Polysorbate 80 solution between 0.5 hour and 3 hours as a result of celecoxib crystallization. The supersaturation level in the HCl pH 3 solution and the STC-containing solution was relatively constant for a period of 48 hours in agreement with observations that the amorphous suspensions prepared using these two media were stable for more than 48 hours. The supersaturation level in the Poloxamer 188 buffer increased steadily over the first 4 hours and then decreased slowly from 4.2 to 2.8 over the next 44 hours. This slow decrease in supersaturation could be the result of celecoxib crystallization; however the growth of the celecoxib crystals in the Poloxamer 188 containing solution must be very slow and the presence of small amount of celecoxib crystals was not detectable by the polarized microscope in the stability study discussed above. Lastly, drug leaching in the Triton X100 buffer is minor with a very low supersaturation of 1.6 reached at 0.5 hour which was maintained over the next 47.5 hours. The concentration of HPMCAS was evaluated in four of the solutions as a function of time and results from the polymer leaching study are shown in Figure 8. Considerable polymer leaching was observed in the SDS buffer with polymer concentrations increasing by more than 3 orders of magnitude relative to the reference pH 3 HCl solution; in the latter medium the polymer is poorly soluble with a concentration of only a few micrograms/mL. In STC solutions, the polymer solubility was enhanced relative to in the HCl solution, but to a lower extent than for SDS. In Triton X100 solutions the polymer concentration profile was similar to that obtained for the HCl solution.


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10 SDS 0.25% HCl pH 3 STC 0.75%

8

Supersaturation

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Figure 7. Celecoxib supersaturation in aqueous solution with and without surfactants as a function of time at 25°C. The increase in solution concentration resulted from leaching of celecoxib from the ASD particles, while subsequent decreases are due to crystallization. All supersaturations were calculated based on the equilibrium solubility of celecoxib Form III in the liquid medium of interest and dividing the measured solution concentration by this value.



1000

HPMCAS Concentration (µg/mL)

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SDS 0.25% STC 0.75% Triton X100 0.025% HCl pH 3

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Figure 8. Concentration of HPMCAS in the different media as a result of polymer leaching from suspended solid dispersion particles. The concentration of polymer is plotted on a logarithmic scale.

DISCUSSION Many ASDs are formulated with a polymer that has a low solubility in an acid environment, with HPMCAS being one of the widely used acid-insoluble polymers. Thus addition of the ASD to an acidic solution will result in a suspension, particularly at high polymer loadings (where dissolution is polymer controlled) due to the slow dissolution rate of the polymer. This situation arises when a solid oral ASD dosage form is taken orally and the gastric pH is low, as well as when a suspension of ASD particles in a low pH medium is formulated for dosing to animals via oral gavage. For the ASD to perform effectively in vivo, it is vital that the suspension is stable to crystallization over the relevant time scale. Given that surfactants are commonly added to ASD


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formulations, either to the solid dispersion particle itself, or to the suspending medium in the case of a formulated suspension, it is essential to understand the impact of these materials on ASD stability. Based on the results shown in Table 1, surfactant choice is clearly critical in impacting the crystallization kinetics of celecoxib ASDs. The stability of the amorphous suspensions prepared in media containing different types of surfactant followed the order: STC ≈ Triton X100 ≈ no surfactant > Poloxamer 188 > Polysorbate 80 > SDS. Thus in the absence of surfactant, the celecoxib ASDs had good stability in an aqueous suspension, however, the stability was compromised by the addition of some surfactants such as SDS but not by other surfactants such as Triton X100. It is proposed that there are two major factors contributing to the observed surfactant effect namely: (1) the impact of the surfactant on the solute nucleation kinetics from the supersaturated solution that evolves following leaching of the drug and (2) the influence of the surfactant on leaching of drug which in turn is impacted by how much the surfactant enhances the polymer leaching.

The impact of surfactant on celecoxib nucleation It has been demonstrated previously that additives in solution such as polymers and surfactants can influence the nucleation of the crystallizing compounds11a, 14. Among the five surfactant studied, Polysorbate 80, Poloxamer 188 and SDS enhance the nucleation of celecoxib from the solution at a constant supersaturation while Triton X100 and STC inhibit nucleation. Interestingly, the three surfactants with nucleation enhancing effects all have a chain-like hydrophobic tail while the two surfactants which inhibit nucleation both have a bulky hydrophobic group. There are multiple interfaces in the suspension of amorphous dispersion on



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which surfactants can assemble into a Langmuir Blodgett film. It was reported in previous studies that such surfactant assemblies can promote crystallization by acting as templates for the nucleation and growth of crystals15. Berman et. al. also showed that a Langmuir Blodgett film of acidic polydiacetylene can cooperatively align with the nucleating calcite to promote its nucleation due to the flexibility of the liner polymer chain16. It is therefore conceivable that the linear hydrophobic chains of Polysorbate 80, Poloxamer 188 and SDS have more flexibility to align in the optimal configuration to promote the nucleation of celecoxib. In contrast, Triton X100 and STC both have a bulky hydrophobic group and lack flexibility; hence the templating effect would not be possible for these compounds and compound-surfactant interactions may be responsible for the observed inhibition of celecoxib nucleation. As well as enhancing the nucleation of celecoxib, SDS also causes significant leaching of the drug from the particle into the aqueous medium. The substantial leaching results in a high level of supersaturation which of course also favors nucleation. Thus the amorphous suspension containing SDS is the least stable. The presence of Polysorbate 80 also greatly enhances the nucleation of celecoxib, however the extent of drug leaching is lower, and thus the amorphous suspension is slightly more stable relative to the SDS containing medium. In contrast, although Poloxamer 188 enhances the crystallization of celecoxib from aqueous solution and causes similar level of drug leaching to that observed for Polysorbate 80 systems, the amorphous suspension prepared using this surfactant were stable for at least 48 hours. It was suspected that HPMCAS, which also leaches into the aqueous phase might alter the impact of surfactants on the crystallization induction time of celecoxib. Therefore, induction times were determined for solutions containing both surfactant (SDS, Polysorbate 80 and Poloxamer) and 3 µg/mL HPMCAS The polymer concentration was chosen as the minimum polymer concentration that


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could be anticipated to be present in the aqueous medium as it is just below the amount of polymer observed to leach into solution at pH 3 (see Figure 8). Nucleation induction times for the surfactant containing solutions in the presence and absence of HPMCAS are shown in Figure 9. The small amount of HPMCAS had no impact on the induction times for the systems containing SDS and Polysorbate 80 within experimental error. However, in the case of Poloxamer 188, the nucleation induction time in the presence of HPMCAS is significantly longer than that with no polymer. This most likely explains the extended stability of amorphous suspensions that contain Poloxamer 188, in particular since the actual HPMCAS concentration is likely to be higher than that tested in this study. STC and Triton X100 not only inhibit the nucleation of celecoxib and but also only result in moderate or minor drug leaching leading to lower levels of supersaturation. This yields ASD suspensions that are stable for prolonged periods of time, at least 48 hours. Thus the influence of the surfactant on both drug leaching from ASD particles into the aqueous medium and the drug substance nucleation kinetics both appear to play a critical role in the determining the stability of the amorphous suspension whereby it is clearly desirable to minimize leaching.



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Figure 9. Nucleation induction times of celecoxib from media containing SDS, Polysorbate 80 and Poloxamer 188, with HPMCSAS (red) and without HPMCAS (blue) at S=5.

It is likely that the extent of drug leaching is related to the enhanced solubility of the polymer in the presence of the surfactant. In other words, the dissolution of the polymer in the medium leads to elevated concentrations of the drug, since the drug release appears to be largely controlled by the polymer properties, most likely due to the relatively low drug loading. As illustrated by Figure 8, HPMCAS has very low solubility at pH 3 and polymer leaching is minimal. However, SDS greatly enhanced the solubility of the polymer. The most likely mechanism for the solubility enhancement of the polymer is the formation of polymer-surfactant complexes. It has been reported by Nilsson that HPMC and SDS can form complexes in aqueous solution; at low polymer concentration individual SDS clusters are formed on a single polymer chain while at high polymer concentration SDS clusters are shared by two or more polymer chains17. Qi et al. have demonstrated the existence of HPMC-SDS complexes using fluorescence spectroscopy as


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well as noting that the presence of an ionic surfactant enhances the dissolution of an ASD formulation.18 Crystallization route. There are two potential routes for crystallization that can occur in an amorphous suspension: from the bulk solution following dissolution of the drug or from the matrix/surface of the solid dispersion particles. The amorphous solid dispersion particles formulated with HPMCAS are stable for over 48 hours in HCl solution (pH = 3). Only after more than 7 days in aqueous media was crystallization observed and it seems to originate from the matrix/surface of the solid dispersion particles (Figure 10). For toxicity testing, the suspension should be stable for a few hours; celecoxib ASDs would meet this requirement when formulated in a simple pH-adjusted medium. However the addition of a surfactant is often a necessity to improve the wettability and flowability of the formulation. Clearly using the “wrong” type of surfactant can reduce the stability of the amorphous suspension leading to a loss of efficacy due to crystallization of the compound, as observed for SDS and Polysorbate 80 in the case of celecoxib. SDS and Polysorbate 80 facilitate the crystallization of celecoxib molecules that have dissolved into the liquid medium, as evidenced by the presence of long needles floating in the solution that are not associated with the solid dispersion particles. In contrast, surfactants such as STC and Triton X100, do not compromise the stability of the amorphous suspension and therefore should be assessed as alternative wetting agents. The amorphous suspensions prepared in media containing these two surfactants were stable for at least 7 days and showed crystallization from the surface and or the matrix of the solid dispersion particle rather than from the bulk solution.



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Figure 10. Polarized microscopic image of celecoxib/HPMCAS (DL 33.3 w/w%) solid dispersion suspended in Triton X100 0.025% buffer for 7 days. The birefringence of the particles suggested that crystallization has happened in/on the surface of the spray dried particles.

CONCLUSIONS Surfactant choice has been found to be a critical parameter in determining the stability of amorphous solid dispersion suspensions to crystallization. Surfactants can impact ASD suspension stability both by promoting crystallization of the drug in the aqueous medium, as well as facilitating leaching of the drug from the solid dispersion particles. SDS, and Polysorbate 80 were found to reduce the stability of ASD suspensions to crystallization, while STC and Triton X100 yielded stable suspensions. Surfactants such as SDS, Polysorbate 80 and Poloxamer 188 which have unbranched hydrophobic tails were found to enhance the nucleation of celocoxib from aqueous solutions, while surfactants with bulky groups, STC and Triton X100 inhibited nucleation. Drug leaching was correlated to enhancements in polymer solubility in the presence of the surfactants. Thus, the impact of surfactants


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on the stability of ASD formulations towards crystallization needs to be carefully considered and a risk benefit analysis of using surfactants performed. Acknowledgements and Disclosures Merck is thanked for providing financial support for this study. We would like to acknowledge Michael Lowinger, R. Peter Wuelfing, and Gwen Kuehl for helpful discussions. REFERENCES

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TOC Graphic

Induction time (min)

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400 350 300 250 200 150 100 50 0

273 >960 273

Celecoxib crystals in presence of SDS 7

12

29

88 41


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Impact of Surfactants on the Crystallization of Aqueous Suspensions

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