Dissolution Characteristics of Fast-Crystallizing β-Lapachone within

Article pubs.acs.org/crystal

Dissolution Characteristics of Fast-Crystallizing β‑Lapachone within Different Semicrystalline Microstructures of Polyethylene Glycol or Poly(ethylene oxide)−Poly(propylene oxide)−Poly(ethylene oxide) Triblock Copolymer Zhen Chen, Chengyu Liu, Ling Zhang, and Feng Qian* School of Pharmaceutical Sciences and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, P. R. China ABSTRACT: The dissolution rate of a crystalline solid dispersion could be influenced by multiple factors including its composition, the form and crystallinity of the containing drug, and its microstructure. In this study, crystalline dispersions of a fast-crystallizing drug, β-lapachone (β-LAP), within the matrix of polyethylene glycol (PEG) or poly(ethylene oxide)−poly(propylene oxide)−poly(ethylene oxide) triblock copolymer (Poloxamer 188), were obtained by spray drying. The drug−polymer interaction, crystallization kinetics of the drug and polymer upon solvent evaporation, and the microstructure of the crystalline dispersion were investigated by various techniques including differential scanning calorimetry, polarized optical microscopy/hot-stage, scanning electron microscopy, wide-angle X-ray diffraction, small-angle X-ray scattering, atomic force microscopy, X-ray photoelectron spectroscopy, etc. The intrinsic dissolution rate of the β-LAP/P188 crystalline dispersion was almost 30 times faster than that of β-LAP/PEG, which was attributed to the difference in their crystalline microstructures, rather than any differences in their drug crystal form, size, or crystallinity. During solvent evaporation, PEG crystallized first and β-LAP molecules were uniformly restricted in the interlamellar or interfibrillar regions of PEG due to the strong β-LAP/PEG interaction and then crystallized into perfect crystals that homogeneously distributed and densely packed within the PEG matrix. Such microstructure prevented a fast dissolution of β-LAP/PEG dispersion. In comparison, β-LAP crystallized simultaneously with P188 without being confined by a preformed crystalline microstructure of the polymer. The reciprocal crystallization inhibition between β-LAP and P188 caused substantial defects in the β-LAP crystals. At the same time, β-LAP molecules were expelled to the interfibrillar region or to the growth front of P188 crystals, resulting in a heterogeneous drug distribution in the disordered and loosely packed microstructure. Such microstructure and crystalline defects of drug crystals synergistically facilitated the fast dissolution of β-LAP/P188 crystal dispersions. We conclude that molecular interaction between drug and polymer, as well as the crystallization kinetics of each component within the binary system, critically affect the microstructure and the dissolution performance of crystalline solid dispersions. another drug.11−13 However, formulation challenges such as low drug loading, physical instability, and excipient caused side effects remain major hurdles for further translational evaluation. Considering patient compliance and the high dose of β-LAP, oral formulation is certainly an even more attractive approach for β-LAP,14,15 if the oral bioavailability and formulation stability could be achieved. As a compound that is nonionizable, modest lipophilic (logP = 2.5), and extremely fast crystallizing, common formulation approaches such as salt formation or improved wetting are not applicable or not sufficient. Amorphous solid dispersion with 20 wt % of β-LAP in HPMC-AS was also prepared in our lab by spray drying;

1. INTRODUCTION β-Lapachone (β-LAP), first obtained from the heartwood of Red Lapacho (Tabebuia impetiginosa) in the Amazonian rainforest and other parts of South America, is a promising novel anticancer agent that could be activated by NADP(H) quinone oxidoreductase 1 (NQO1), an enzyme overexpressed in many type of cancers.1−4 β-LAP was also reported to have antifungal, antiviral, antibacterial, antipsoriatic, and antiinflammatory effects.5 However, the low solubility and high projected human dose, as well as the short blood t1/2 (24 min) and the narrow therapeutic window, significantly limited its clinical evaluation.6−10 Several intravenous formulations of βLAP have been developed and evaluated in preclinical and/or clinical studies, including inclusion complex with hydroxylpropyl β-cyclodextrin, encapsulation within poly(ethylene glycol)-b-poly(D,L-lactic acid) micelles alone or together with © XXXX American Chemical Society

Received: June 9, 2016 Revised: August 1, 2016

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DOI: 10.1021/acs.cgd.6b00879 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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however, it crystallized within 1 week under ambient conditions, and dissolution showed little improvement compared with crystalline suspensions, due to the fast crystallization tendency of β-LAP either in the solid dispersion or in the supersaturated solution. Crystal size reduction,16−18 especially nanosizing,19−24 appears to be one of the few potentially viable formulation strategies remaining to be evaluated for oral delivery of β-LAP, which was reported to have only one orthorhombic crystal form with an acicular crystal habit, regardless of the crystallization methods.25,26 Crystalline solid dispersions wherein drug crystallized within a semicrystalline polymer matrix to form size-reduced (sometimes nanosized) crystals have long been reported, and it has been observed that various microstructures could be obtained with the modulation of different semicrystalline polymers, such as polyethylene glycol (PEG) and poly(ethylene oxide)− poly(propylene oxide)−poly(ethylene oxide) (PEO−PPO− PEO) triblock copolymers (Poloxamer or Pluronic).27−36 For instance, fenofibrate/PEG eutectic formation reduced the fenofibrate crystal size under 10 μm thus improved the drug dissolution rate significantly.34 Naproxen/PEG crystalline dispersion prepared at 25 °C was found to dissolve faster than that prepared at 40 °C, due to the smaller naproxen crystal size within the material crystallized at lower temperature.31 Depending on the physicochemical properties of the drug, crystal sizes from nanometric to micrometer scale could be formed within the interlamellar or interfibrillar regions of PEG, thus to produce different crystal forms, size, and microstructures with different dissolution properties.28 With the inclusion of an amorphous and hydrophobic PPO segment, the crystallization kinetics and the polymer microstructure of Poloxamer (PEO−PPO−PEO) are different from that of PEG homopolymer.37−40 During the lamellae formation of Poloxamer, amorphous PPO segments reduce the crystal perfection and decrease the crystallinity. The PPO segments could also affect the distribution and crystallization of drug based on the molecular interaction between drug and polymer.41 In the present study, PEG 3350 and Poloxamer 188 are selected as two semicrystalline polymer matrixes to prepare crystalline dispersions of β-LAP. We studied the interaction between β-LAP/PEO and β-LAP/PPO, the crystallization kinetics of β-LAP/polymer binary systems, and the microstructure of obtained crystalline dispersions. Moreover, the intrinsic dissolution rates of the crystalline dispersions were determined and compared, and the relationship between the microstructure and the dissolution rates of the crystalline solid dispersions was investigated.

Figure 1. Molecular structures of β-LAP, PEG, and P188. and the solution was fed into a Nano Spray Dryer B-90 equipped with a vibrating mesh spray technology and an electrostatic particle collector (BÜ CHI, Switzerland). The spray drying process was performed with the following conditions: inlet temperature 52 °C, outlet temperature 32 °C, N2 flow rate of 110 L/min, spray mesh with 5.5 μm aperture size, pump mode number 2, spray rate of 100%, and 37 mbar of atomization pressure. After spray drying, materials on the electrostatic particle collector were collected and passed through a sieve with 74 μm, vacuum-dried for 24 h, and then stored in a desiccator at room temperature. The amount of β-LAP in the spraydried materials was analyzed by HPLC. 2.3. Wide-Angle X-ray Diffraction (WAXRD). (1) Crystal Form and Crystallite Size. The pure β-LAP, PEG 3350, and β-LAP/polymer solid dispersion powders and tablets were measured at room temperature by a Bruker D8-Advance X-ray diffractometer equipped with Cu Kα radiation (λ = 1.54 Å), and scanned from 2θ = 5° to 28° at a speed of 1°/min, with a step size of 0.01°. The crystallite size in the direction perpendicular to (102) reflection based on the diffraction peak at 2θ = 9.54° was calculated by the Scherrer equation as described in the previous work.41 (2) Crystallinity. The K value method proposed by Chung was applied to calculate the crystallinity of β-LAP in spray-dried solid dispersions,42−44 using CaCO3 as the internal standard substance in this study. The blends were measured by a X’Pert3 Powder X-ray diffractometer (PANalytical, Inc. U.K.) equipped with Cu Kα radiation (λ = 1.54 Å) and scanned at a step size of 0.013° and step time of 300 s. 2.4. X-ray Photoelectron Spectroscopy (XPS). X-ray photoelectron spectra were performed on the ESCALab 250Xi (Thermo Scientific, America) with a 6 channeltron hemispherical sector analyzer under a base pressure of 3 × 10−10 mbar in the analysis chamber, using 200 W monochromatic Al Kα radiation. The X-ray spot for SAXPS analysis was 500 μm, and as typical, the hydrocarbon C 1s line at 284.8 eV from adventitious carbon was used for energy referencing. All spectra analysis and curve fitting were completed by the Avantage Software (Thermo). The surface atomic concentration of the C−O group in the polymer and CO group in β-LAP determined from integrated peak intensities was used to calculate the β-LAP concentration at the surface of spray-dried β-LAP/polymer powders. 2.5. Scanning Electron Microscopy (SEM). The surface morphologies of solid dispersion powders and tablets after intrinsic dissolution were analyzed using a scanning electron microscope (FEI Quanta 200, Netherlands) operated at an excitation voltage of 15 kV. Samples were mounted onto copper stage and coated with gold before observation. 2.6. Small-Angle X-ray Scattering (SAXS). Spray-dried powders were measured at ambient temperature by a Rigaku Smartlab X-ray diffractometer equipped with Cu Kα radiation (λ = 1.54 Å) operated at 40 kV and 150 mA. PEG, P188, β-LAP/PEG, and β-LAP/P188 crystalline dispersions were compressed in a predrilled hole of a copper sheet with a thickness of 0.93 mm. The scanning angle was from 0.09° to 2.5° (2θ), and the total scan time was 15 min. 2.7. Polarized Optical Microscopy (POM). A Zeiss Axio Imager A2m microscope was used to observe the crystal growth rate and

2. EXPERIMENTAL SECTION 2.1. Materials. β-Lapachone was purchased from Pharmaron company (China) and further purified by recrystallization in isopropanol and dried under a vacuum. PEG (average Mn 3350) and PEO−PPO-PEO triblock copolymer (Poloxamer 188, P188) were provided by Dow Chemical Company (Midland, MI). Micronized βLAP crystals and polymers used for physical mixture were obtained through sieves with 30 and 74 μm openings, respectively. The molecular structures of β-LAP and polymers are shown in Figure 1. Acetonitrile (HPLC grade) and formic acid (HPLC grade) used for the mobile phase, as well as dichloromethane (analytical grade) used for spray drying, were purchased from Beijing Chemical Works (Beijing, China). 2.2. Preparation of β-LAP/Polymer Solid Dispersions by Spray Drying. The β-LAP/polymer (20/80, w/w) blend was dissolved in dichloromethane with a total concentration of 5 wt %, B

DOI: 10.1021/acs.cgd.6b00879 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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material morphology. Crystallization of the spin-coated film was monitored under POM at room temperature immediately after the preparation. The in situ observation of isothermal crystallization processes was performed on a Linkham LTS420 hot stage. Samples were kept for 1 min at melting temperature and then cooled to different preset temperatures at a cooling rate of 50 °C/min. 2.8. Atomic Force Microscopy (AFM). The surface morphologies of β-LAP solid dispersions in PEG and P188 were investigated by AFM. Thin films of drug/polymer were prepared by spin-coating 5 wt % solution onto a silicon substrate solution. After the solvent was removed completely under a vacuum, the films were analyzed by an AFM (Nanoscope VIII Multimode Digital Instruments) at room temperature. 2.9. Differential Scanning Calorimetry (DSC). A TA Instruments DSC Q2000 (New Castle, DE) was used to measure the melting point depression of β-LAP in different polymer matrix at a heating rate of 10 °C/min to detect the drug−polymer molecular interaction. The melting behavior of the crystalline dispersions was studied at a heating rate of 10 °C/min from 30 to 130 °C. The crystallization of pure β-LAP and PEG was conducted at a cooling rate of 10 °C/min after isothermal at 130 °C for 1 min. 2.10. Intrinsic Dissolution Studies of β-LAP/Polymer Dispersions. Tablets of several systems were prepared for the intrinsic dissolution studies, including β-LAP/polymer SD (spray drying) (20/ 80 w/w), β-LAP/polymer PM (physical mixture) (20/80 w/w), and pure components. The powders were compressed by a carver press (C-NE 3888, USA) at a pressure of 500 kgf. The obtained tablets (diameter of 11 mm) were sealed with wax within syringe tubes, exposing only one surface to the dissolution medium. The intrinsic dissolution of various tablets were carried out using an USP II apparatus (Automated lab systems, ADT8, U.K.) under sink conditions, with a dissolution medium of 500 mL of Milli-Q water (Merck Millipore, Germany) at 37 °C and a paddle speed of 110 rpm. At the predetermined time points of every 1 min, 0.5 mL dissolution solution was withdrawn and filtered with 0.45 μm syringe filter, being used to analyze the intrinsic dissolution behaviors of different systems. The concentration of β-LAP in the dissolution medium was analyzed by high-performance liquid chromatography (HPLC) (Shimadzu LC-20AT, Kyoto, Japan) with a UV−vis spectrophotometer and an analytical column of SymmetryShield RP-18 (5 μm, 150 mm × 4.6 mm). The mobile phase, acetonitrile/Milli-Q water (65/35 v/v), was pumped at a flow rate of 1.2 mL/min at 30 °C. The injection volume was 10 μL, and the PDA detector was set at a wavelength of 257 nm. The concentration of polymer in the dissolution medium was measured by an evaporative light scattering detector (ELSD). Briefly, the dissolution medium was separated by a gradient method using HPLC (1260 series, Agilent Technologies, Santa Clara, CA, USA) with a polystyrene gel column of RS pak DS413 (3.5 μm, 150 mm × 4.6 mm, Shodex, Japan) at 25 °C. The mobile phase was acetonitrile (1‰ formic acid)/water (1‰ formic acid) (40/60 v/v), pumped at a flow rate of 0.5 mL/min and an injection volume of 15−50 μL for the PEG system and 10−40 μL for the P188 system. The polymer concentration was determined using an ELSD detector (380-LC, Agilent Technologies, USA), based on the preestablished standard curve of ELSD scattering intensity vs. polymer concentration. The solubility of crystalline β-LAP in water, as well as in the presence of PEG or P188 at 1, 3, or 5 mg/mL, was determined by suspending an excess amount of β-LAP crystals in the solution, followed by vortexing for 1 min, sonication for 5 min, and then shaking at 37 °C for 24 h using an orbital shaker (Burrell wrist action shaker, model 75). The suspension was subsequently centrifuged at 12 000 rpm (Changsha Pingfan Co., Ltd., TG16W, China) for 5 min, and the supernatant was analyzed by HPLC/UV−vis to obtain the drug concentration.

known that the crystal form is critically affecting the solubility of drug crystals and the dissolution rate of formulations. The WAXRD profiles of spray-dried β-LAP/PEG or P188 solid dispersions, as well as pure micronized β-LAP and PEG, were collected and shown in Figure 2. In comparison with the

Figure 2. WAXRD profiles of micronized PEG and β-LAP, spray-dried β-LAP/polymer powder and tablet by compression to identify the crystal form, size, and crystallinity of β-LAP in solid dispersions.

characteristic scattering peaks in the reference scattering patterns of β-LAP crystal or PEG crystal, we concluded that β-LAP crystallizes into the same form as reported in previous literature. The crystal cell structure is reported with parameters as a = 12.8995 Å, b = 6.8681 Å, c = 26.6419 Å, and α = β = γ = 90°. Drug crystallite size is another important factor that might influence the solubility and dissolution rate, illustrated by the Ostwald−Freundlich equation and the Noyes−Whitney equation.45 Shown in Table 1, the crystallite size of β-LAP Table 1. Crystallite Sizea and Crystallinity of β-LAP in Different Crystalline Dispersions

a

system

crystallite size (nm)

wt %

β-LAP/PEG β-LAP/P188

92.7 83.8

20.8 22.6

A reflection peak at 2θ = 9.54° is selected for both systems.

perpendicular to the (102) reflection, that is, the shorter dimension of the needle-like crystals, was determined to 92.7 or 83.8 nm, respectively. The crystallinity of β-LAP in PEG or P188 matrix was determined to be 20.8 and 22.6 wt %, respectively, almost the same as the total β-LAP amount (20 wt %), indicating complete β-LAP crystallization within both polymer matrix. In summary, the crystal form, size, and crystallinity of β-LAP within PEG or P188 are all the same/very similar, which are not expected to cause any major differences in their intrinsic dissolution rates. 3.2. Distribution and Microstructure of β-LAP Crystals in Crystalline Dispersions. Surface chemistry of the crystalline dispersions was analyzed by XPS, which detects the concentration of oxygen (O) with different biding energies in CO groups (in β-LAP only) and C−O groups (in polymers). On the basis of this measurement, the surface βLAP concentration in β-LAP/PEG and β-LAP/P188 dispersions was calculated to be 23.3 and 72.4 wt %, respectively (Table 2). It is interesting to note that spray-dried β-LAP/PEG crystalline dispersion has approximately the same surface (23.3

3. RESULTS AND DISCUSSION 3.1. Crystal Form, Crystallite Size and Crystallinity of β-LAP in Spray-dried Crystalline Dispersions. It is wellC

DOI: 10.1021/acs.cgd.6b00879 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Table 2. Oxygen Composition in Different Groupsa and Crystallinity of β-LAP in Solid Dispersions

acicular crystals with a relatively short length of 5 μm. Furthermore, these β-LAP crystals also appeared to be hollow and less regular with wide size distribution, and lack smooth crystal surfaces as commonly observed on perfect crystals. These relatively large and defective β-LAP crystals easily dispersed in the water after the removal of P188 (Figure 3d inset). 3.3. Crystal Structure of the Polymers within the Crystalline Dispersions. Figure 4 compared the Lorentz-

atomic % system

Ols (C−O)

O1s(CO)

wt %

β-LAP/PEG β-LAP/P188

28.9 17.7

3.0 11.7

23.3 72.4

a

The average peak biding energy of O 1s in C−O group of polymer and that in CO group of β-LAP is 532.37 and 533.36 eV, respectively.

wt %) and bulk (20 wt %, theoretical value) β-LAP concentration, while the β-LAP/P188 crystalline dispersion has a 3−4 times higher β-LAP concentration (72.4 wt %). In other words, β-LAP/PEG had a much more homogeneous drug distribution compared with the β-LAP/P188 system. Figure 3a,b shows the surface morphology of the β-LAP/ PEG and β-LAP/P188 crystalline dispersions under SEM. The

Figure 4. Lorentz-corrected 1D SAXS profiles of PEG, P188, β-LAP/ PEG, and β-LAP/P188 crystalline dispersions at ambient temperature.

corrected 1D SAXS profiles of the pure polymers and the βLAP/polymer crystalline dispersions to reveal the packing structure of the polymers, as well as the length of a long period consisting of alternative crystalline and amorphous layers with different electron density. For pure P188 and β-LAP/P188 dispersion, two scattering peaks were observed at q = 0.042 and 0.081 Å−1, corresponding to the first and second order Bragg’s peaks of polymer lamella, respectively. The long periods, calculated by L = 2π/q, were the same at 15.0 nm for both systems. However, Figure 5 showed that the melting temperature (peak position) of P188 depressed from 53 °C (blue line) to 51 °C (magenta line) in the presence of β-LAP. It was ascribed to the lamellar layer thinning, as well as considerable defects in the lamella region in the β-LAP/P188 dispersion.

Figure 3. Surface morphology of spray-dried (a) β-LAP/PEG and (b) β-LAP/P188 materials under SEM observation, and the β-LAP crystals after PEG (c) or P188 (d) was removed by water washing. The insets in (c) and (d) are POM pictures of the collected β-LAP crystals. The smaller and regular β-LAP crystals in the PEG systems showed the high tendency of aggregation (c), while the larger and irregular β-LAP crystals in the P188 systems were easily dispersible. Note: the pores underneath the β-LAP crystals in (d) belong to the filter membrane.

surface of β-LAP/PEG powder was smooth and flat (Figure 3a), where the long side of β-LAP crystals was approximately parallel with the powder surface, and the two crystalline components were indistinguishable from each other. However, the surface of the β-LAP/P188 powder was largely rough and irregular. β-LAP crystals were clearly visible embedded in the P188 polymer matrix in a random manner (Figure 3b), which indicated a relatively heterogeneous distribution of the β-LAP crystal within the β-LAP/P188 solid dispersion. To compare the morphology of β-LAP crystals within two different polymer matrixes, the solid dispersions were washed with water to remove the polymers, and the remaining β-LAP crystals were collected by 0.45 μm filter membranes, vacuumdried, and subjected to POM and SEM observation. Figure 3c,d shows the morphology and microstructure of the β-LAP crystals isolated from the PEG and P188 systems, respectively. β-LAP crystals collected from the β-LAP/PEG dispersions were

Figure 5. DSC curves of PEG, P188, β-LAP/PEG, and β-LAP/P188 crystalline dispersions heated at 10 °C/min. The inset shows the DSC curves of β-LAP/PEG (lower) and β-LAP/P188 (upper) at temperature above 90 °C. D

DOI: 10.1021/acs.cgd.6b00879 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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In contrast, only a very weak scattering peak appeared at q = 0.055 Å−1 in PEG profile, while it was hardly detectable in the β-LAP/PEG profile. However, a large endotherm corresponding to the melting of the PEG crystals was measured in these two systems during the DSC heating process (Figure 5). We speculate that this apparently contradictory phenomenon was caused by the formation of a uniform and densely packed crystalline structure without alternative crystalline and amorphous layers with a different electron density, which made the materials featureless by SAXS. Meanwhile, the long periodic structure of PEG crystal might also have been disturbed by the penetration of a needle-like β-LAP crystal in the binary system, causing the disappearance of the tiny scattering peak. The depression of PEG melting temperature compared with pure PEG was likely contributed by this crystal penetration, i.e., eutectic structure. Besides, the highest melting temperature of the four systems was detected in the spray-dried β-LAP/PEG system as shown in Figure 5 (inset), reflecting a more regular and perfect structure than others. 3.4. Intrinsic Dissolution Characteristics of β-LAP Containing Crystalline Solid Dispersions. As shown in Figure 6a and Table 3, the intrinsic dissolution rate of the micronized β-LAP was 1.84 μg/min/cm2, the slowest among all materials. Simply blending the micronized β-LAP crystals with PEG or P188 significantly increased the β-LAP dissolution rate ∼1034 and ∼599 fold, respectively. Surprisingly, the spraydried β-LAP/PEG showed a much slower β-LAP dissolution rate than the physical blend, with a merely ∼40 fold increase compared to the micronized β-LAP crystals, while the spraydried β-LAP/P188 showed further dissolution enhancement than the physical blend, with a ∼934 fold increase of dissolution rate compared with the micronized β-LAP crystals. As discussed earlier, the β-LAP crystal form, size, and crystallinity of the SD β-LAP/PEG and β-LAP/P188 powders were the same or very similar and thus could not be the major causes for the drastic β-LAP intrinsic dissolution differences. We studied two more potential affecting factors, i.e., the solubility of β-LAP in the presence of different polymers, and the wettability of two SD materials. The equilibrium solubility of β-LAP in the presence of PEG or P188 with polymer concentrations of 1, 3, or 5 mg/mL was measured to be ranging from 44 to 52 μg/mL, with the lowest solubility of 44 μg/mL detected in 1 mg/mL P188 solution and the highest solubility of 52 μg/mL in 5 mg/mL PEG solution. The solubility of βLAP in PEG is slightly higher than that in P188 at the same polymer concentration. As for the wettability, we found that βLAP/PEG was in fact more wettable compared with the βLAP/P188 SD tablet, based on the comparison of their contact angles (Table 3). Also, the contact angles of the binary systems roughly satisfied the physical superposition principle according to their composition. In summary, β-LAP solubility or wettability of the SD materials still cannot explain the difference in the intrinsic dissolution rates of β-LAP/PEG and β-LAP/ P188 SD tablets. Figure 6b compares the intrinsic dissolution rates of the polymers by themselves, from the physical mixtures with βLAP, and from the spray-dried β-LAP/polymer crystalline dispersions. Pure PEG showed a much faster dissolution rate (5754 μg/min/cm2) than P188 (1823 μg/min/cm2), and physical mixing with β-LAP showed no impact on the dissolution rate of either PEG or P188. However, PEG dissolution rate from β-LAP/PEG crystalline dispersion decreased 9 fold to 669 μg/min/cm2, while the P188

Figure 6. Intrinsic dissolution of the drug and polymer from different materials, including pure micronized β-LAP crystals, pure PEG, pure P188, β-LAP/PEG PM (physical mixture), β-LAP/P188 PM, β-LAP/ PEG SD (spray dried crystalline dispersion), and β-LAP/P188 SD. The polymer release was normalized to its weight percentage in the solid dispersions (i.e., divided by 4). The released concentration (μg/ mL) of β-LAP, polymer, and the ratio of polymer to drug is plotted in (a), (b), and (c) respectively.

Table 3. Normalized Intrinsic Release Ratea of β-LAP and Polymer from Different Tablets and the Water Contact Angles of the Tablets normalized release rate (μg/min/cm2) system

polymer

β-LAP PEG P188 β-LAP/PEG PM β-LAP/PEG SD β-LAP/P188 PM β-LAP/P188 SD

5754 1823 6036 669 1892 1412

β-LAP 1.84

1902 58 1102 1718

contact angle 80.3 16.5 35.9 33.0 47.3

a

Normalized release rate was obtained by correcting the release rate of polymer according to the weight composition, assuming same density for crystalline drug and polymer.

E

DOI: 10.1021/acs.cgd.6b00879 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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dissolution rate from β-LAP/P188 crystalline dispersion only slightly decreased 1.34 fold to 1412 μg/min/cm2. To help understand the dissolution mechanism of the drug/ polymer crystalline dispersions, the ratio between intrinsic dissolution rates of polymer and drug was calculated and compared in Figure 6c. For the β-LAP/P188 system, the dissolution rate ratio between P188 and β-LAP was relatively constant, fluctuating narrowly around 1.8 and 0.6 for physical mixtures (PM) and spray dried crystalline dispersions (SD), respectively. The relative constant polymer/drug dissolution rate ratio suggested that drug dissolution in these cases was mostly controlled by the dissolution of polymer and solubility of drug crystals in the dissolution medium. Different drug crystal sizes and morphologies might have also contributed to the different drug dissolution rates between β-LAP/P188 PM and SD systems: β-LAP crystals in the PM were larger (∼30 μm) and more regular, which were obtained from recrystallization and mesh screening, while β-LAP crystals in the SD system were smaller (