Impact of Nisoldipine Crystal Morphology on Its ... - ACS Publications

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Impact of Nisoldipine Crystal Morphology on Its Biopharmaceutical Properties: A Layer Docking Assisted Study Dinesh Kumar,† Rajesh Thipparaboina,† and Nalini R Shastri*,† †

National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad, 500037, India S Supporting Information *

ABSTRACT: Crystal morphology or habit modification can have profound influence on the pharmaceutical and biopharmaceutical properties of active pharmaceutical ingredients. The effect of crystallization medium on nisoldipine (NSL) crystal habit was studied, wherein modified habits were observed in solvent system, methanol, and solvent antisolvent system of acetonitrile−IPA. Modified crystal habits of NSL were in correlation with the simulated habits in terms of their shape and aspect ratio. The comparative dissolution rate of the recrystallized NSL habits was in the order of NSL-M (NSL recrystallized with methanol) > NSL-AI (NSL recrystallized with acetonitrile and IPA) > NSL (plain NSL). A statistically significant (p < 0.05) enhancement in the dissolution rate of NSL-M was observed on comparison with NSL. NSL-M also exhibited a significantly higher Cmax than NSL in an oral bioavailability study. The study of specific surface area values of important facets of NSL-M revealed a notable enhancement of the crystal facet (1 0 1). The facet (1 0 1) was found polar which probably resulted in enhancement in the rate of dissolution and consequently the oral bioavailability of NSL-M. This outcome was also supported by surface chemistry determination from the morphology growth model and hirshfeld surface analysis. The research methodology used here is a step in the direction of a designed crystal habit modification, the scope of which can be extended to other molecules.

1. INTRODUCTION Modifications in crystallization medium and procedure can influence the crystallization course causing changes in crystal morphology or habit which can further affect material characteristics and their pharmaceutical performance.1,2 Crystal habit is important from manufacturing point of view as it can significantly affect active pharmaceutical ingredient (API) properties like flow rate, compressibility, dissolution rate, and bioavailability.3,4 Many APIs show poor solubility and dissolution rate, which reduce their applicability in oral delivery. There are different techniques to improve the pharmaceutical and biopharmaceutical properties of APIs which include micronization, cosolvency, salts, complexes, solid dispersions, suspensions, and various crystallization-based techniques.5,6 The broad aim of this project was to investigate systematically how surface properties of a crystal habit can influence the dissolution rate and oral bioavailability. Nisoldipine (NSL) is a calcium channel blocker and mainly indicated for hypertension, heart failure, and angina pectoris. NSL belongs to BCS Class II as it shows poor aqueous solubility and low bioavailability. Enhancing the pharmaceutical and biopharmaceutical properties using crystal habit approach for other drugs is wellreported.7−9 However, the impact of anisotropic characteristics of NSL on the pharmaceutical properties (dissolution rate) and its subsequent pharmacokinetic behavior (oral bioavailability) has not been reported. These issues are important for NSL due to its poor rate of dissolution and poor oral bioavailability. Crystal habit modification for this drug can hence be an effective technique to counter dissolution and bioavailability problem.10 This forms the basis of our current research. In addition, the selected model drug NSL exhibits good crystallization ability, which makes it an ideal API for crystal © XXXX American Chemical Society

habit modification studies. Molecular dynamics based layer docking approach is an important tool to simulate and predict the crystal habit.11 Simulation approach has been widely used to design crystal habit of the desired dimensions.12,13 Hence, a joint approach of simulation and experimental strategy can be important in obtaining desired crystal habit. The work described here includes recrystallization of NSL with screened solvents/antisolvents followed by microscopic examination. The solvent systems with least aspect ratio were further characterized using advanced characterizations tools like FTIR, DSC, TGA, and P-XRD to examine any solid form change. Molecular dynamics and surface docking approach was employed for prediction of crystal habits. The nature of surface functional moiety on specific crystal facet, the nature of crystallization medium, and their combined impact on crystal morphology were thoroughly described. The crystals with modified habits were investigated for their impact on dissolution rate. The crystals with the improved dissolution rate were further selected to study their impact on oral bioavailability. The impact of aspect ratio and surface area/ volume ratio (S/V) on the dissolution rate was also studied. The simulated habit properties were useful in understanding the facet-dependent properties. The novelty of research work lies in molecular dynamics studies of NSL habits and correlating their facet properties to pharmaceutical and biopharmaceutical performance. It was concluded that methanol and acetonitrile−IPA, in this study, interacts differentially with different crystal facets, resulting in modification of NSL Special Issue: Polymorphism & Crystallisation 2015 Received: September 21, 2015

A

DOI: 10.1021/acs.oprd.5b00299 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Å). The data were recorded over a scanning range of 2° to 50° at a step time of 0.045 steps/0.5 s. 2.4. In Vitro Dissolution Studies. Recrystallized NSL samples were passed through BSS sieve no. 44 and then through BSS sieve no. 60. The crystals that passed through the sieve no. 44 and retained on the sieve no. 60 (44/60) were weighed and measured optically for particle size. The particle sizes were reported in terms of D10, D50, and D90 cumulative percentage undersize (Supplementary Table 1). The screened crystals were then used for the dissolution study to minimize the impact of crystal size on the dissolution rate. The dissolution study was carried out in an USP Apparatus II at 100 rpm (n = 3). The weighed quantities of crystals (20 mg) were then added to 900 mL of the dissolution medium (0.1% v/v SLS in distilled water) kept at a temperature of 37 ± 0.5 °C. The samples from dissolution medium were withdrawn at specific time intervals though a syringe connected with a 0.45 μm size membrane filter. The drawn volume of dissolution medium was immediately replaced by an equal volume of fresh dissolution medium. These samples were then evaluated and quantified for NSL concentration using a validated UV method at 238 nm. A plot of cumulative drug release vs time was obtained, and the dissolution efficiency (DE) at various time points was calculated by the given formula to compare various dissolution profiles.14,15

crystal habit and their related properties. This study brings about a newer perspective in the field of crystal habit modification, which can be helpful in solvent/additive screening for crystallization to obtain crystals with desired morphology that can result in better pharmaceutical and biopharmaceutical performance.

Figure 1. NSL: (a) Chemical structure; (b) crystal structure.

2. EXPERIMENTAL SECTION 2.1. Materials. NSL and lacidipine were kindly gifted by Apotex Pharmachem (Bangalore, India) and Dr. Reddy’s Lab, India, respectively. Methanol and acetonitrile was purchased from Merck, India. Isopropyl alcohol (IPA) was purchased from Finar, India. In-house Millipore water was used for all experiments. Unless specified otherwise, analytical grade chemicals were used in all experiments. Amber-colored glasswares and Eppendorf tubes were used during experiments and for storage. 2.2. Recrystallization Experiments. The protocol used in crystallization experiments was developed based on NSL solubility data in various solvents. The selected solvents were maintained at their respective boiling temperature. A slight excess amount (as calculated from solubility data) of NSL was mixed in 4 mL of the selected solvent. Recrystallization was also carried out with an antisolvent to solvent ratio of 1:4. The solutions were filtered and allowed to cool to attain required supersaturation. The rate of evaporation was controlled via an inverted funnel plugged with cotton. After 24 h, these crystals were collected, dried, and stored in the amber colored bottles. These stored crystals were then used for further characterizations. 2.3. Solid State Characterization. NSL crystals were examined by optical microscope (Nikone TiU coupled with NIE software). The particle sizes and aspect ratios were determined (n = 100). DSC (differential scanning calorimetry) analysis of NSL crystals was done using Mettler Toledo Stare DSC system that was calibrated using Indium standard. The sample cells were purged with dry nitrogen gas at the flow rate of 40 mL/min. The accurately weighed samples (∼5 mg) were scanned in aluminum pans at a heating rate of 10 °C/min, in temperature range of 25−200 °C. The presence of any solvent/ degradation in NSL crystals upon heating was examined by weight loss in thermogravimetric analysis (TGA) using Universal, V47A, TA Instruments, on an accurately weighed samples (5−10 mg) loaded in crucibles made of alumina that were heated at a rate of 10 °C/min in temperature range of 25−300 °C under dry nitrogen purge at the flow rate of 60 mL/min. PXRD of NSL crystal samples were carried out at room temperature on X’Pert Pro PANalytical X-ray powder diffractometer, using Ni filtered Cu Ka radiation (λ = 1.5406

D

DE =

∫t y dt y100 t

(1)

2.5. In Vivo Pharmacokinetic Studies. Female SD rats (2−3 months of age, 200−300 g) were housed according to the CPCSEA guidelines in the Animal Facilities of NIPER, Hyderabad. Approval for animal study was granted by the IAEC (Institutional Ethical Committee for Animal Experimentation). Two group of rats (n = 6) were fasted for 12 h. For comparison of pharmacokinetic parameters, selected crystals and free drug were given to the rats via oral gavage (10 mg/kg). Blood samples (∼500 μL) were collected from the retro orbital plexus of animals at time points of 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h after dosing. Plasma was then harvested by centrifugation at 3500 g for 5 min, transferred to fresh tubes containing 30 μL of heparin, and stored at −20 °C. To 100 μL of plasma sample, 25 μL of internal standard (lacidipine) was mixed and then vortexed for 1 min. An aliquot of 375 μL of methanol was added as a protein precipitant, vortexed for 5 min, and then centrifuged at 5000 g for 10 min. A 100 μL supernatant was filtered and then analyzed for NSL content by validated HPLC method. The e2695 Waters HPLC system consisted of a pump, automated injector, and a 2998 PDA UV detector. Calibration curves were plotted over the concentration range of 10−1000 ng/mL and were used for the conversion of the NSL/lacidipine plot to NSL concentration. Mobile phase employed for HPLC analysis was acetonitrile and 10 mM ammonium acetate phosphoric acid solution (65:35). Retention time (Rt) of NSL and internal standard (lacidipine) was found to be 5.1 and 9.8 min, respectively. NSL was detected and quantified at 238 nm, and the column (GraceSmart RP18, 25 cm × 0.46 cm) was maintained at room temperature. The in vivo data were analyzed by the Kinetica software (Thermo Scientific Inc.). Different pharmacokinetic parameters like total area under the curve (AUC)0−12, half-life (t1/2), peak plasma concentration (Cmax), and time taken to reach the peak B

DOI: 10.1021/acs.oprd.5b00299 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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plasma concentration (Tmax) were determined. The relative oral bioavailability of the selected NSL-M crystals after oral administration was calculated in comparison to NSL suspension. 2.6. Statistical Analysis. All in vitro and in vivo results were reported as mean ± standard deviation. One-way ANOVA was performed using SigmaStat (version 3.5), The test was considered statistically significant when the p value was found less than 0.05. 2.7. Computer Simulation Studies. A crystallographic information file (CIF) of NSL was obtained from CSD (Cambridge Structural Database reference 7207563, monoclinic P21/n, a: 10.789, b: 15.651, c: 11.934, α: 90, β: 102.51, γ: 90). All molecular simulations and habit generation were executed using crystal bundle of Materials Studio 6.1. Geometry optimization and energy minimizations were carried out using COMPASS force field along with forcite algorithm. Face list was generated using BFDH, which gave different hkl plane and dhkl values of respective facets. The modeling method for crystal morphology calculation was based on modified attachment energy method (MAE). The details of modeling protocol are provided as Supporting Information. Analysis of intermolecular interactions by the hirshfeld surface was employed to study interaction in crystallization medium. The intermolecular interactions of NSL were quantified by hirshfeld surface analysis using Crystal Explorer (Version 3.0) on the crystal structure. Hirshfeld plot is a tool for visualization and understanding the intermolecular interactions. Important intermolecular and intramolecular interactions can be studied using different hirshfeld surfaces and relative 2-D fingerprint plots.

Table 1. NSL Recrystallization with Screened Solvents and Antisolvent antisolvent

solvent

without antisolvent

chloroform ethyl acetate DCM ethanol methanol acetonitrile chloroform ethyl acetate DCM ethanol

hexane

methanol

IPA

acetonitrile chloroform ethyl acetate DCM ethanol methanol acetonitrile

a

solubility (mg/mL) 95 124 80 70 78 130

crystal habit precipitate thin needles ppt. thin needles rods long needles precipitate thin needles precipitate thin long needles rods (nonuniform) long needles precipitate thin needles precipitate needles (nonuniform) rods cum needles rods

average aspect ratio ± SD 9.47 ± 3.70 8.86 ± 2.92 4.66 ± 0.94 11.46 ± 4.77 10.19 ± 2.80 13.94 ± 3.46 7.86 ± 2.72 11.90 ± 2.43 10.24 ± 2.14 10.96 ± 0.327 8.23 ± 2.16 6.31 ± 1.41

All values are expressed as mean ± SD (n = 100).

docking method was introduced by incorporation of solvent molecules during the simulation steps. NSL showed good solubility in chloroform, DCM, methanol, ethanol, ethyl acetate, and acetonitrile, whereas it was observed to be poorly soluble in IPA and hexane (Table 1). The solvent and solvent−antisolvent systems, which gave crystals with least aspect ratios, were chosen for further experiments (Table 1). Habits were successfully modified with methanol. Thick rod crystals with an aspect ratio 4.66 ± 0.94 were observed for NSL recrystallized with methanol (NSL-M) (Figure 2a, Table 1). The simulated morphology obtained in this solvent system was

3. RESULTS AND DISCUSSION 3.1. Crystallization Experiments and Simulation Studies. NSL morphology was simulated using three vacuum morphology models and compared with the experimentally grown crystal habits. First vacuum morphology was generated from BFDH that gave 8 important facets along with their respective hkl, dhkl, and percentage surface areas. The interplanar spacings of various low index faces are tabulated in Supplementary Table 1, while Supplementary Figure 1a shows the NSL morphology based on the BFDH model. Result shows that the morphologically important crystal facets were (0 1 1), (1 0−1), (1 1 0), (0 2 0), (1 1 −1), and (1 0 1). According to growth morphology (GM) model, the crystal faces consisted of (0 1 1), (1 0 1), and (1 1 0) planes, in which (0 1 1) plane with 31.24% of total facet area, and (1 0 1) plane with 25.32% of facet area were observed as the important facets. Similarly, from the equilibrium morphology (EM) model, the crystal faces consisted of (1 0−1), (0 2 0), (1 1−1), and (1 0 1) facets, in which (1 0−1) facet with 18.83% of total facet area, (0 2 0) facet with 13.91% of total facet area, and (1 0 1) facet with 13.49% of facet area were important. The aspect ratio calculated by BFDH model for NSL was 1.37. The calculated aspect ratio was 1.65 and 1.50 for growth morphology model (Supplementary Figure 1b) and equilibrium morphology model (Supplementary Figure 1c), respectively. However, the predicted habits from the above three models were found to be different from the experimental habits (Table 1). This deviation in the experimental habits from the simulated habit was ascribed to the absence of real experimental environment that was present during crystallization experiments. Hence, to improve the prediction ability of the simulated model, layer-

Figure 2. NSL: (a) Experimental habit with methanol; (b) predicted habit with methanol. C

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M and NSL-AI, statistically no significant difference was observed in the aspect ratio of experimental morphology and simulated morphology (p > 0.05), which were also evidenced by microscopic examinations. These results also indicated that solvent and solvent/antisolvent system changed the growth rate of the NSL crystal facets anisotropically. The crystal morphology of the experimentally recrystallized NSL in the presence of solvent and antisolvent showed changes according to the properties of crystal growth medium, as evident from the optical images. The relative presence of polar and nonpolar moiety was examined on different facets of NSL crystal habit obtained by the growth morphology model (Supplementary Figure 2 and Supplementary Table 2). In crystal slices, the (0 1 1) facet showed a large number of nonpolar carbon containing functional moieties, while the (1 0−1) facet also showed the presence of nonpolar carbon, aromatic ring, and polar oxygen. Similarly, the (1 1 0) facet showed an equal abundance of nonpolar carbon along with one oxygen containing functional group, and (0 2 0) facet showed the presence of nonpolar carbon containing functional groups, aromatic ring, and oxygen containing functional groups. The (1 1−1) facet showed majority of nonpolar carbon containing functional groups along with few oxygen containing functional groups whereas (1 0 1) facet showed that the polar functional groups were abundant in comparison to carbon containing nonpolar functional groups. The (1 2−1) facet displayed an abundance of nonpolar carbon containing functional moieties and aromatic ring. The orientation of molecules on each facet of a NSL crystal is dissimilar because of its structural variation. The relative presence of functional moieties of different nature on facets of simulated NSL morphology allowed the correlation of its crystal surface property with properties of medium used for crystallization. Solvents of dissimilar dielectric constants used during the crystallization can influence their crystal habits.17,18 Under specific crystallization medium, growth of a particular crystal facet may be inhibited, or the other facets may grow rapidly.19 It is reported that solvents of polar nature are preferentially adsorbed by polar facets and nonpolar solvents by nonpolar facets.19 Consequently, the polar facets are thought to be prevailing when polar solvents are used while nonpolar facets are dominating when nonpolar solvents are employed.20 It was hence evident from the facet surface area values of NSLM (Figure 4), that methanol induced a remarkable enhancement of growth on (1 0 1). The crystal facet (1 0 1), due to the major presence of polar functional moieties dominated in a polar environment of methanol. In contrast, combination of acetonitrile and IPA induced the expansion of a nonpolar facet (1 1−1) in NSL-AI. The surface slice of (1 1−1) dominated in nonpolar medium due to the presence of larger number of nonpolar functional moieties on its surface. The change in the surface area of (0 2 0) was however small, as it shows nearly equal existence of polar and nonpolar functional moieties (1 carboxyl and 2 methyl). Two-dimensional plots to visualize the three-dimensional distance information between the hirshfeld surfaces and atoms external (de) and internal (di) to that particular surface (Figure 5) was obtained. The highest percentage of contacts was found between H···H atoms (54%) which are presumed not to make a large impact on the crystallization (Supplementary Figure 3). Most of the difference comes from the O···H (26.1%) contacts, which are polar when compared to nonpolar C··H contacts (15.7%). The same conclusion was drawn from the surface

also nearly rod shaped with an aspect ratio of 4.94 which was significantly similar to the experimentally grown habit (Figure 2b). The most important facets were (0 1 1), (1 0−1), (0 2 0), and (1 0 1) with their respective surface area of 17.91%, 25.86%, 17.90%, and 38.31%. The aspect ratio obtained with methanol was 4.66 which was least when compared to other solvents used for recrystallization but not ideal (∼1); hence recrystallization was attempted using various antisolvents. The solvent/antisolvents, which gave crystals with lowest aspect ratios, was selected for further studies (Table 1). Other solvent systems and their combinations were not chosen because of their higher aspect ratio.16 Habits were modified successfully with acetonitrile as solvent and antisolvent IPA (NSL-AI), whereas with other solvent/ antisolvent systems irregular shaped crystals were obtained. A rod-shaped crystal habit with an average aspect ratio of 6.31 ± 1.41 was obtained experimentally, for NSL-AI (Table 1, Figure 3a), while a rod shape morphology with an aspect ratio 5.41

Figure 3. NSL: (a) Experimental habit with acetonitrile as solvent and IPA as antisolvent and (b) predicted habit with acetonitrile as solvent and IPA as antisolvent.

was simulated by modified attachment energy method when similar crystallization environment was provided (Figure 3b). The important crystal facets were (0 2 0), (1 1−1), and (1 0 1) and with a surface area of 33.98%, 50.53%, and 14.81% respectively (Figure 4). From the above studies related to NSL-

Figure 4. Surface areas of important facets in modified crystal habits of NSL. D

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Figure 5. Relative contributions to Hirshfeld surface for intermolecular close contacts.

Figure 6. Dissolution profile of selected NSL crystals (n = 6).

NSL-M irrespective of similar size distribution (Supplementary Table 3). The dissolution enhancement was in the order of NSL-M > NSL-AI > NSL which was confirmed from the dissolution efficiency tabulated at various time points (Supplementary Table 4). This difference in the dissolution rate can be attributed to the functional group anisotropy on the facet surface of various habits. The surface area values indicated that methanol induced a notable enhancement in the growth of (1 0 1) crystal facet. The facet (1 0 1) with ∼39% of total facet area was polar as observed from the surface chemistry study which probably led to enhancement in the dissolution rate of NSL-M. This became more evident as the proportion of polar facet (1 0 1) in NSL-AI was only ∼15%. In contrast, combination of acetonitrile and IPA induced the growth of (1 1−1) facet in NSL-AI (∼50.53% of total facet area) that was predominantly nonpolar in nature. Facet (1 1−1) dominated in comparatively nonpolar crystallization medium due to the abundance of nonpolar functional moieties and probably resulted in less enhancement of dissolution rate. This nonpolar facet (1 1−1) was totally absent from crystals grown with methanol (NSL-M). Thus, the enhanced polar facet (1 0 1) and reduced nonpolar facet (1 1−1) in NSL-M and vice versa in NSL-AI probably resulted in differential extent of their enhanced dissolution rate. The expansion in polar facet was also coupled with their higher S/V (1.38 for NSL-M and 1.20 for NSL-AI). The higher S/V ratio of NSL-M is attributed to anisotropy and less aspect ratio, which could have resulted in enhanced rate of dissolution. Chen et al. conducted an experiment on crystal habits and showed that the dissolution rate can depend on habit as differential surface chemistry cause differences in their respective free surface energy.22 From their study, they concluded that modified habit could be taken advantage of in enhancing the dissolution rate of drugs with limited solubility in aqueous medium. Chow et al. have also suggested that the habit of doped crystals played a significant role in the enhancement of intrinsic dissolution rate of phenytoin due to the presence of majority of polar facets.23 3.4. In Vivo Study. A significant improvement (p < 0.05) in dissolution efficiency was observed with NSL-M (DE360 = 60.9), when compared with NSL (DE360 = 48.2) and NSL-AI (DE360 = 51.4); hence NSL-M was selected for in vivo study. Cmax varied significantly between NSL and NSL-M (Figure 7). The Cmax of NSL was 1.94 ± 0.45 μg/mL. On the other hand, NSL-M exhibited an improved Cmax value of 3.1 ± 0.49 μg/mL. A significant (p < 0.05) 159% enhancement in the Cmax (peak plasma concentration) was observed in case of NSL-M when compared to NSL. This enhancement in peak plasma concentration indicates the enhanced absorption rate of NSL-

chemistry study wherein it has been observed that polar methanol was preferentially adsorbed by the polar crystal facets (1 0 1) which become dominant in NSL-M. The opposite phenomena was observed for NSL-AI where nonpolar functional groups showed preferential adsorption on facet (1 1−1) which was predominantly nonpolar. The resultant interaction was responsible for the final crystal morphology. Results from the Hirshfeld surface analysis hence supported the outcome of the crystal surface chemistry study. 3.2. Solid State Characterization of Selected Crystals. The NSL samples were analyzed by different solid-state characterization techniques to rule out any crystallization induced polymorphism or pseudo polymorphism. FT-IR peaks of untreated NSL and modified NSL habits are shown in Supplementary Figure 4. All FT-IR spectra were superimposable, and the characteristics absorption bands of NSL was seen in all the spectra, indicating that the modified crystals and the untreated NSL were similar in their structural arrangement and conformations. Similarly, percentage transmittance of FTIR showed absence of any hydrates/solvates. The DSC thermograms of all recrystallized samples were similar to that of plain NSL (Supplementary Figure 5). The DSC curve of NSL crystals showed a single sharp endotherm at 151 °C corresponding to the reported melting point of NSL. Similarly, other recrystallized samples also showed single melting point in the range of 151−152 °C. Thus, a single melting point without any additional endothermic transition ruled out the likelihood of any other reported polymorphs of NSL.21 Absence of any hydrate/solvate formation was concluded as no solvent endothermic peak was detected in the DSC thermograms. All of these findings were further supported by TGA analysis (Supplementary Figure 6) wherein no weight loss was observed until the melting point of the drug. In PXRD results (Supplementary Figure 7), characteristic peaks of NSL were present in all recrystallized NSL samples. A slight reduction in the intensity of few NSL crystal samples could be probably due to the different preferred orientations of the crystals, which may have occurred due to their different habits. Thus, from all solidstate characterization studies, it was concluded that no polymorphs, hydrates, or solvates were formed, and merely habit modifications had occurred on recrystallization. 3.3. Comparative Dissolution Rate. NSL recrystallized from methanol (NSL-M) showed considerable improvement in the dissolution rate (Figure 6). Similarly, NSL recrystallized from acetonitrile, and IPA (NSL-AI) also demonstrated enhanced dissolution rate; however, the extent was relatively less when compared to the dissolution rate improvement by E

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Hyderabad, India and instrumental support from Sipra laboratories, Hyderabad, India.

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ABBREVIATIONS MD, molecular dynamics; NSL, nisoldipine; DSC, differential scanning calorimetry; TGA, thermogravimetric analysis; pXRD, powder X-ray diffraction

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(1) Rasenack, N.; Muller, B. W. Int. J. Pharm. 2002, 244, 45−57. (2) Su, C. S.; Liao, C. Y.; Jheng, W. D. Chem. Eng. Technol. 2015, 38, 181−186. (3) Blagden, N.; De Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617−630. (4) Mishra, M. K.; Sanphui, P.; Ramamurty, U.; Desiraju, G. R. Cryst. Growth Des. 2014, 14, 3054−3061. (5) Bikiaris, D. N. Expert Opin. Drug Delivery 2011, 8, 1501−1519. (6) Bikiaris, D. N. Expert Opin. Drug Delivery 2011, 8, 1663−1680. (7) Rasenack, N.; Müller, B. W. Int. J. Pharm. 2002, 244, 45−57. (8) Tiwary, A. Drug Dev. Ind. Pharm. 2001, 27, 699−709. (9) Modi, S. R.; Dantuluri, A. K. R.; Puri, V.; Pawar, Y. B.; Nandekar, P.; Sangamwar, A. T.; Perumalla, S. R.; Sun, C. C.; Bansal, A. K. Cryst. Growth Des. 2013, 13, 2824−2832. (10) Garekani, H. A.; Sadeghi, F.; Badiee, A.; Mostafa, S. A.; RajabiSiahboomi, A. R.; Rajabi-Siahboomi, A. R. Drug Dev. Ind. Pharm. 2001, 27, 803−809. (11) Liang, Z.; Yi, Q.; Wang, W.; Han, X.; Chen, J.; Le, Y.; Wang, J.; Xue, C.; Zhao, H. Comput. Chem. Eng. 2014, 62, 56−61. (12) Shi, W.; Xia, M.; Lei, W.; Wang, F. J. Mol. Graphics Modell. 2014, 50, 71−77. (13) Salvalaglio, M.; Vetter, T.; Mazzotti, M.; Parrinello, M. Angew. Chem., Int. Ed. 2013, 52, 13369−13372. (14) Kumar, D.; Chirravuri, S. S.; Shastri, N. R. Int. J. Pharm. 2014, 461, 459−468. (15) Chella, N.; Shastri, N.; Tadikonda, R. R. Acta Pharm. Sin. B 2012, 2, 502−508. (16) Tiwary, A. K. Drug Dev. Ind. Pharm. 2001, 27, 699−709. (17) Lee, T.; Lin, H. Y.; Lee, H. L. Org. Process Res. Dev. 2013, 17, 1168−1178. (18) Tung, H.-H. Org. Process Res. Dev. 2013, 17, 445−454. (19) Nokhodchi, A.; Bolourtchian, N.; Dinarvand, R. Int. J. Pharm. 2003, 250, 85−97. (20) Shariare, M. H.; Blagden, N.; Matas, M. d.; Leusen, F. J. J.; York, P. J. Pharm. Sci. 2012, 101, 1108−1119. (21) Yang, C.; Zhang, Z.; Zeng, Y.; Wang, J.; Wang, Y.; Ma, B. CrystEngComm 2012, 14, 2589−2594. (22) Chen, J.; Sarma, B.; Evans, J. M. B.; Myerson, A. S. Cryst. Growth Des. 2011, 11, 887−895. (23) Chow, A. H. L.; Hsia, C. K.; Gordon, J. D.; Young, J. W. M.; Vargha-Butler, E. I. Int. J. Pharm. 1995, 126, 21−28.

Figure 7. Plasma concentration−time profile of plain NSL and NSLM.

M. The AUC0−12h of NSL-M crystals was about 1.51 times significant increase in the total plasma concentration, when compared to that of NSL suspension (p < 0.05), indicative of improved extent of absorption. The improved dissolution rate of NSL-M hence provides a justification for the observed enhancement in the oral bioavailability, which in turn can be easily explained with the crystal surface chemistry where proportion of polar facet increased in NSL-M when compared to NSL.

4. CONCLUSION Crystal habits of NSL were modified and correlation was drawn between lab grown and simulated habits. Interpretations from solid-state characterization indicated that no polymorphic transformation or hydrates/solvates formation occurred and merely habit modifications occurred during recrystallization. NSL recrystallized with methanol (NSL-M) resulted in significant dissolution rate enhancement. This improvement in the dissolution rate of NSL-M translated into oral bioavailability enhancement. Morphology growth model based surface analysis and hirshfeld surface were useful tools for evaluating modified habit and their importance in pharmaceutical as well as in biopharmaceutical performances. This level of improvement is significant to biopharmaceutical performance of APIs with poor aqueous solubility and poor bioavailability.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.5b00299. Data based on vacumm morphology models; quantifications of surface chemistry, particle size distribution, and data related to dissolution efficiency; Hirshfeld surface plot and solid state characterization (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*Tel.: +91-040-23423749. Fax: +91-040-23073751. E-mail: [email protected], [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Authors acknowledge the financial support from the National Institute of Pharmaceutical Education & Research (NIPER), F

DOI: 10.1021/acs.oprd.5b00299 Org. Process Res. Dev. XXXX, XXX, XXX−XXX