Article pubs.acs.org/OPRD
Development of Pharmaceutically Acceptable Crystalline Forms of Drug Substances via Solid-State Solvent Exchange Srividya Ramakrishnan,*,† Sesha Reddy Yarraguntla,† Subba Reddy Peddireddy,† Sundara Lakshmi Kanniah,†,§ Vamsi Krishna Mudapaka,† Lalita Kanwar Shekhawat,†,∥ Sudarshan Mahapatra,† Amjad Basha Mohammad,† Peddy Vishweshwar,† and Peter W. Stephens‡ †
Integrated Product Development, Dr. Reddy’s Laboratories Ltd., Hyderabad 500090, Telangana, India Department of Physics and Astronomy, Stony Brook University, Stony Brook, New York 11794-3800, United States
‡
S Supporting Information *
ABSTRACT: In the pharmaceutical industry, solid form screening plays an important role to discover forms that exhibit desired physicochemical properties for drug product development. This work describes an approach to meet this objective by the transformation of undesirable solvates to hydrates or cosolvates with water via solid-state solvent exchange. Case studies of two drug substances, imatinib mesylate and linagliptin, are discussed, where linaglipitin methanol/ethanol solvate was converted to an iso-structural hydrate and, similarly, imatinib mesylate methanol−water cosolvate was converted to a predominantly watercontaining cosolvate. Through quality by design based optimization, temperature and relative humidity were identified as critical process parameters that impacted the rate of solvent exchange during humidification. In addition, crystallization parameters that impacted the crystal size were found to play a key role in determining the extent of solvent exchange. This unexpected effect of crystal size was investigated through single crystal structure elucidation and molecular modeling, which showed the solvent to be residing in channels oriented along the length of the crystal. The dimensions of these channels determined the ease of solvent exchange by controlling the rate and extent of diffusion of solvent molecules. With these case studies, this paper provides insight on robust process development for solid-state solvent exchange with an in-depth understanding of molecular level phenomena and critical process parameters.
1. INTRODUCTION Polymorphs, which are two or more crystalline phases of the same molecule that have different arrangements or conformations of the molecules in the crystal lattice,1 can have different physicochemical properties that impact bioavailability, processability, or overall drug product performance.2,3 In the pharmaceutical industry, there is an extensive effort to discover solid forms of drug substances that are optimal for drug product development. While several crystalline forms are discovered during solid form screening, very few exhibit the desired stability, bioavailability, and physical properties suitable for formulation development. Since solid form screening often results in solvates which are pharmaceutically undesirable due to ICH limits on solvent content, the transformation of such solvates to desolvated forms could result in a desirable solid form. However, attempts to desolvate can result in conversion to an amorphous or a crystalline form with different structures if the lattice is not stable in the absence of the solvent.4 In some cases, the structure remains intact even after solvent loss creating isomorphic desolvates, but these are at a higher energy state than the solvated forms and exhibit tendency for resolvation or structural relaxation.5 An alternative to desolvation is the transformation of a solvate to a pharmaceutically acceptable solvate/hydrate via solvent exchange. Solvent exchange can occur through a cooperative mechanism wherein the lattice framework remains intact6 or through a destructive and reconstructive mechanism where the lattice structure is completely altered.7 The rate of solvent exchange has been shown to be dependent on the dimension of © XXXX American Chemical Society
the channel with respect to the solvent molecule and the strength of interactions.8 While the mechanism of solvent exchange has been studied, there have been few cases reported where solid-state solvent exchange has been explored as a strategy to develop crystalline forms of drug substances. This paper presents case studies of two different drug substances, imatinib mesylate and linagliptin, where alcohol solvates were converted to pharmaceutically acceptable cosolvate/hydrate through solid-state solvent exchange. In both these cases, a cooperative mechanism was observed with the lattice framework intact. The critical process parameters that affect the kinetics and effectiveness of solvent exchange were identified through design of experiments (DoE). Mechanistic insight at a molecular level was obtained through single crystal structure elucidation and molecular modeling, which explained the differences observed between imatinib mesylate and linagliptin.
2. EXPERIMENTAL SECTION 2.1. Experimental Setup. Crystallization experiments were conducted in cylindrical, jacketed 1 L reactors equipped with a retreat curve impeller and connected to Julabo or Huber cryostats for temperature control. Lab-scale humidification experiments were conducted in a humidification chamber (Jeiotech, model TH-TG-180) with temperature and humidity Received: March 24, 2017
A
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2.2.6. Water Content. Water content of the samples were analyzed using Titrando-901 model (Metrohm AG, Switzerland) with Karl Fischer reagent and methanol as the diluent. 2.3. Modeling. Morphology predictions for all available single crystal structures of imatinib mesylate and linagliptin were carried out by using morphology module of Material studio 8.0 (BIOVIO). The following parameters were chosen for this calculationForce field: Dreiding, Electrostatic terms: Ewald summation with 1 × 10−3 kcal/mol of accuracy and 0.5 Å of buffer width. The van der Waals terms were atom based summation with a cubic spline truncation, 12.5 Å cutoff distance, 1 Å spline width, and 0.5 Å buffer width. The hydrogen bond terms were atom based summation with a cubic spline truncation, 4.5 Å cutoff distance, 0.5 Å spline width, and 0.5 Å buffer width. Electronic charge used the QEq method. The atomic volume was determined from a van der Waals surface created using Material Studio 8.0 (BIOVIO). The following parameters were chosengrid interval: 0.75 Å, van der Waal scale factor: 1.0. The single point energy was calculated for all crystal structures and solvent molecules using DMol3 module of Material Studio (BIOVIO)-8.0. The calculation was performed by using local density approximation (LDA) with a Perdew− Wang correlation (PWC) functional. The double numerical plus d-functions (DND) basis sets were used in the calculation. The integration accuracy, SCF tolerance, and k-point set (1 × 1 × 1 mesh) were kept at medium level. The core electrons were treated with DFT Semi-Core Pseudo Potentials (DSPPs). A smearing of 0.005 Ha was used to speed up the convergence.
control. The results from DoE were analyzed using Design Expert-7 (Stat-Ease, USA). 2.2. Characterization. 2.2.1. Powder X-ray Diffraction. The crystalline forms were characterized by powder X-ray diffraction using a PANalytical X’Pert PRO instrument equipped with an X’celerator detector. The X-ray source was Cu Kα radiation (λ = 1.5418 Å) with tube voltage of 45 kV and tube current of 40 mA. 2.2.2. Single Crystal X-ray Diffraction. Single crystal X-ray data (SCXRD) were collected on Bruker APEX2 using Mo−Kα radiation (λ = 0.7107 Å). Imatinib mesylate single crystal data were collected at 100 K and linagliptin at 293 K. Data reduction was performed using SAINT/XPREP software. Crystal structures were solved and refined using SIR92 and SHELXL-97 with anisotropic displacement parameters for non-H atoms. Hydrogen atoms bonded to nitrogen were experimentally located through the Fourier difference electron density maps in both of the crystal structures. All C−H atoms were geometrically fixed. Crystallographic parameters of both structures are tabulated in Table S1. 2.2.3. Synchrotron X-ray Diffraction. Powder X-ray diffraction data was collected at ambient temperature using the X16C beamline of the National Synchrotron Light Source at Brookhaven National Laboratory. All samples were sealed into glass capillaries of nominal 1.5 mm diameter and spun about their axes for improved powder counting statistics. X-rays of wavelength 0.69984 Å were selected by a Si(111) channelcut monochromator and analyzed by a Ge(111) crystal before a scintillation detector. Peak positions were fitted using locally developed software SP and ASAP. Lattices were indexed from fitted peak positions using the SVD-Index algorithm embodied in TOPAS from Bruker-AXS. The same software was used for ab initio structure solution, supplemented by a structure determination from a single crystal of imatinib mesylate ethanol−water cosolvate (Form X). TOPAS was also used for independent refinements of the structure of each sample. In the Rietveld refinements, the imatinib and mesylate molecules were described by z-matrices with all bond distances and angles taken from the structure of Form X. Molecular positions, orientations, and internal torsions were separately refined. Solvents (methanol or ethanol, as appropriate, and water) were refined with variable occupancy. The refinements of imatinib mesylate and alcohol molecules all had H atoms tethered to the heavier atoms as structurally appropriate. Separate isotropic thermal parameters were refined for the imatinib molecule, the mesylate group, the alcohol, and the presumed water. Synchrotron X-ray diffraction data are tabulated in Table S2. 2.2.4. Scanning Electron Microscopy. Scanning electron microscopy (SEM) images of imatinib mesylate were collected using Hitachi S-3000N with secondary electron detection mode operated at a voltage of 10 kV. SEM images of linagliptin were collected using FEI Quanta 250 SEM equipped with GAD detector operated at a voltage of 30 kV. The samples were mounted on an aluminum metal stub with double-sided adhesive carbon tape. 2.2.5. Gas Chromatograpy Analaysis. Gas chromatography analysis of the samples was performed using Agilent-7890A model equipped with a flame ionization detector. Dimethyl sulfoxide (Biosolve HS grade) was used as diluent; samples were injected into AT-624 column (30 m × 0.53 mm × 5.0 μm) with a helium constant pressure of 2.5 psi and at a 250 °C detector temperature.
3. RESULTS AND DISCUSSION 3.1. Imatinib Mesylate. Imatinib mesylate, an antitumor drug, has several crystalline forms reported by Novartis9 and generic pharmaceutical companies. While Form-β is the marketed form, there was a need from a generic perspective to discover a new crystalline form that could be developed. However, after extensive solid form screening, only a cosolvate containing around 5% methanol and 2% water was discovered, which was quite unstable and would convert to Form-β within a few days of storage at 25 °C. Traditional drying techniques resulted in conversion to amorphous form. To develop a pharmaceutically viable solid form, the possibility of solvent exchange was explored. While it was not possible to grow a single crystal of the cosolvate, a single crystal of a reported ethanol−water cosolvate (Form X)10 that had a similar powder X-ray diffraction pattern was grown, and the structure was solved (Table S1). The structure revealed that ethanol and water were present within channels in the lattice. With the ethanol−water cosolvate single crystal structure as a starting point, the structure determination from powder diffraction (SDPD) was performed on the methanol−water cosolvate using synchrotron X-ray diffraction data. The structure revealed that there are two distinct solvent sites in the structure; neither is fully occupied, and they both display large thermal parameters. Consequently it was not possible to assign them with certainty to either methanol or water on the basis of diffraction data alone. However, the best fit had 0.54 mol of water and 0.88 mol of methanol (1.6% and 4.4% by weight, respectively), which was roughly consistent with the assay upon synthesis (Figure 1). The possibility of replacing methanol in the channel with water through humidification was then explored. This strategy proved successful and resulted in a more stable, predominantly hydrated form of the methanol−water cosolvate (Figure 1). B
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water cosolvate involved reactive crystallization of imatinib base with methanesulfonic acid (MSA) at −5 °C in methanol (10 mL/g), followed by seeding and addition of antisolvent, methyl-t-butyl ether (MTBE, 20 mL/g), at −5 °C. This process resulted in methanol−water cosolvate containing 5−6% methanol and 2−3% water by weight. During humidification, the methanol content decreased to below 2%, while the water content increased to around 5%. The effect of temperature (20−80 °C) and humidity (20−60% RH) on methanol-to-water exchange was studied (Table 1). Table 1. Effect of Humidification on the Methanol Content and Crystalline Form temp/ RH
20% RH
40% RH
20 °C
b
b
30 °C
Form-Y
Form-Ya
methanol: 2.6% water: 5.2% Form-Y methanol: 3% water: 5.3% partial conversion to Form-β methanol: 0.7% water: 7%
methanol: 1.9% water: 5.7% API becomes gummy
55 °C
80 °C
API becomes gummy
60% RH Form-Ya methanol: 1.4% water: 5.5% API turned yellow methanol: 1% water: 8% c
c
a c
Conditions that were favorable for solvent exchange. bNot studied. Unfavorable conditions.
The studies were conducted with the same batch of methanol− water cosolvate containing 5−6% methanol initially. All samples were humidified for 24 h. Both temperature and humidity had a very significant effect on the form as well as effectiveness of solvent exchange. High temperatures and high humidity resulted in the powder becoming gummy, while high temperature and low humidity resulted in conversion to Form-β. While the solid form remained intact at low temperature and low humidity, the rate of solvent exchange was slow. The optimal operating range for solvent exchange was at ambient temperature (20−30 °C) with humidity of 40−55% RH. 3.1.2. Impact of Crystallization on Solvent Exchange. The crystallization process was optimized through DoE using response surface methodology with a face-centered model. Three variablescrystallization temperature (A), agitation speed (B), and antisolvent (MTBE) addition rate (C)were considered for optimization (Table 2). Subsequent to crystallization, all samples were humidified for 1 day at 30 °C, 45% RH, followed by drying under vacuum at 50 °C to remove any superficial water. This secondary drying did not have any impact on methanol content (see Supporting Information, Table S4). The solid form and methanol content (measured by GC) after humidification were monitored as responses. While Form-Y was obtained in the entire experimental space of the DoE, the effectiveness of solvent exchange during humidification was found to be highly dependent on the crystallization process parameters, in particular the antisolvent addition rate and temperature. The addition rate of antisolvent had the highest impact on the methanol content, with faster addition at lower temperatures leading to lower methanol content. Although agitation speed alone did not have much impact
Figure 1. (a) Rietveld refinement of the structure of imatinib mesylate methanol−water cosolvate from synchrotron data. Black dots are observed data; the red line is the fit; the green line is the difference; tick marks are positions of allowed diffraction peaks. (b) Overlay of laboratory PXRD before and after humidification. (c) Crystal structure of methanol−water cosolvate; methanol is shown in green, water (disordered in Wyckoff site 4e) in purple.
This form, with pharmaceutically acceptable methanol content as per ICH Q3C(R6) guideline, was designated as Form-Y. Further, Form-Y was subjected to stability evaluation for three months at different temperatures and relative humidity as per ICH guidelines (5 ± 3 °C, 25 °C/60%RH, and 40 °C/75%RH). The results show that the solid form remained intact, physically as well as chemically, at all conditions (see Supporting Information for stability and thermal characterization, Table S3 and Figure S1.) However, several challenges remained to develop a robust process for transformation of the methanol−water cosolvate into Form-Y as it could not be crystallized directly from water or aqueous solvent mixtures. The effect of crystallization and humidification process parameters on the solid form and kinetics of solid-state solvent exchange was systematically studied through DoE. 3.1.1. Humidification Operating Region for Effective Solvent Exchange. The process to crystallize the methanol− C
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Table 2. Process Variables and Their Ranges Considered for the First and Second DoE parameter crystallization temperature (A) agitation speed (B) addition time of MTBE (C)
range for the first DoE
range for the second DoE
−10 to 5 °C
−20 to −5 °C
200−600 rpm 30−180 min
200−600 rpm 45−180 min
rationale for range selection Crystallization temperature is very critical for the solid state form. Above 5 °C, rapid conversion to Form-β is observed. Mixing is considered as a scale-dependent parameter. If MTBE is added very rapidly, it results in gumming out rather than crystallization, particularly at low temperatures. Hence, the minimum addition time was increased to 45 min for the second DoE.
Figure 2. Contour plots for methanol content (ppm). (a) First DoE with temperature range of −10 to 5 °C at 600 rpm, (b) second DoE with temperature range of −20 °C to −5 °C at 600 rpm. Blue color indicates regions where methanol content is within the desired limit, while progression to green, yellow, and red indicate increasing methanol content.
Figure 3. (a) Pareto chart and (b) half-normal plot of the second DoE indicating the significance of temperature and addition time on methanol content.
on the methanol content, the interaction of agitation speed with addition time and temperature had a significant impact. These results indicated that increasing the addition rate and lowering the temperature further may help to reduce the methanol content below 2%. Hence, a second DoE was conducted with a lower temperature range compared to the first DoE, going down to −20 °C from −5 °C. However, the addition rate was not increased further as faster addition resulted in the material becoming gummy at these low temperatures. The results of the second DoE showed that reducing the temperature range significantly expanded the design space where the methanol content could be reduced below 2%. In fact, below −10 °C, even the addition of MTBE
over 3 h resulted in acceptable methanol levels (Figure 2). The Pareto chart, which displays potentially important effects in decreasing order of significance, and half-normal plot, where all the significant effects are to the right of the origin, are shown in Figure 3. These plots indicate that temperature is the most significant parameter impacting methanol content followed by interaction of temperature and addition time, while the effect of mixing is almost insignificant in the range studied. The effect of crystallization parameters on the rate and extent of solvent exchange can be explained by crystallization kinetics. Both the crystallization temperature and the rate of addition of MTBE directly impact the degree of supersaturation during crystallization. There is a significant drop in solubility of D
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imatinib mesylate Form-Y in methanol from 5 °C to −20 °C (Figure S2 in Supporting Information). As a result, during reactive crystallization of imatinib base to mesylate, the degree of supersaturation is much higher at lower temperatures; that is, the ratio of solution concentration to solubility is around 1.8 at 5 °C but increases to 9.5 at −20 °C in methanol. With addition of MTBE, there is a further steep drop in solubility (Figure S2) indicating that faster addition would lead to higher accumulation of supersaturation. Hence, lower temperatures and faster addition rates of antisolvent lead to a higher degree of supersaturation, favoring nucleation rather than growth, resulting in smaller crystal size distribution. This was evident in SEM images where the slower addition of MTBE resulted in the growth of larger plate-like crystals, whereas faster addition at −20 °C resulted in fine crystals, about 8−10 μm in size (Figure 4). A good correlation was observed between the crystal size, estimated from SEM, and methanol content after humidification (Figure 5). To further confirm the effect of crystal size on the kinetics of solvent exchange, a DoE on the humidification process was conducted with fine (around 5 μm) and coarse (around 15 to 30 μm) crystals. Temperature, relative humidity, and time were selected as variables with the ranges of 25−40 °C, 20−55% RH, and 2−13 h, respectively. The methanol content, which is the best indicator of solvent exchange, was selected as response. For both crystal sizes, all three factors were found to be significant, with higher humidity and temperature driving faster exchange. All two factor interactions were significant for coarse crystals, while only the interaction of humidity and time was found to be significant for fine crystals. The representative contour plots at 40 °C for coarser and finer crystals shown in Figure 6 clearly indicate that the kinetics slow down as the crystal size increases (see Figure S3 in Supporting Information for contour plots at 25 °C). The effect of crystal size on the kinetics and extent of solvent exchange will be further discussed after the second case study on linagliptin. 3.2. Linagliptin. Linagliptin is a DPP-4 inhibitor for treatment of type II diabetes with five crystalline forms (Forms A, B, C, D, and E) reported by Boehringer-Ingelheim.11 During solid form screening, a new crystalline form, Form-I, was discovered by crystallization in ethanol. Similar to the case of imatinib mesylate, this form was found to be a channel solvate, where ethanol, methanol, or water could occupy the
channel. The single crystal structures were solved for both the hydrate (Figure 7, Figure S4 in Supporting Information) and a mixed solvate of ethanol and methanol. Interestingly, the hydrate could not be directly crystallized from water, and the only way to obtain the hydrate was through humidification of the methanol/ethanol solvate. The hydrated Form-I was subjected to stability evaluation as per ICH guidelines and was found to be physically and chemically stable (see Supporting Information for stability and thermal characterization, Table S5 and Figure S5). 3.2.1. Effect of Humidification Process Parameters on Solvent Exchange. The methanol/ethanol solvate could be readily crystallized through cooling crystallization in methanol or ethanol, respectively. To crystallize the methanolate, linagliptin was dissolved in 5 mL/g of 95:5 mixture of methanol−water at about 50 °C. The clear solution was cooled to 30 °C, where seeds were added to initiate nucleation. The slurry was then gradually cooled to 0 °C and filtered. The filtered crystals were the methanol solvate, which were then converted to hydrate by humidification. The humidification process was optimized through a full-factorial design with relative humidity (A), temperature (B), and time (C) as variables. Based on preliminary studies, relative humidity range of 30−90%, temperature range of 25−40 °C, and time spanning from 2 to 24 h were selected for the design. The maximum temperature was set to 40 °C as conversion to Form A was observed above 40 °C. To study the effect of particle size on the rate of solvent exchange, DoE was conducted on two batches of methanol solvate with different particle size. The SEM images of these two batches are shown in Figure 8. The DoE showed that relative humidity and time had a significant effect on the rate of solvent exchange while the effect of temperature was almost insignificant in the range studied (see Figure S6 in Supporting Information for contour plots of methanol content). Interestingly, the relative contributions of relative humidity and time varied depending on the size of the crystals. In the case of the smaller crystals, relative humidity played a more significant role, while for the larger crystals, time was more significant. The relative contributions of the process parameters from the “effects list” in Design Expert are shown in Table 3. As the kinetics of solvent exchange were faster for the small crystals, time played a less significant role compared to the large crystals (Figure 9)
Figure 4. SEM images of Form-Y crystals obtained from experiments conducted with (a) addition of MTBE over 180 min at 5 °C and (b) addition of MTBE over 45 min at −20 °C. E
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3.3. Mechanism of Solvent Exchange. 3.3.1. Morphology and Solvent Mobility. To understand solvent exchange kinetics at a molecular level for imatinib mesylate and linagliptin, Material Studio 8.012 was used to predict the morphology and calculate the single point energy.13 For binding energy and solvent accessibility calculation, the single point energy along with atomic and free volume is calculated for different solvents associated with crystal structures of linagliptin and imatinib
mesylate. The single crystal structure for imatinib mesylate Form-Y could not be obtained; hence the total energy for the same is not reported in this paper. The effect of particle size on solvent exchange can be understood by considering the morphology of the crystals and the alignment and size of the channel. The predicted morphology matches well with experimentally observed morphology for both imatinib mesylate (Figure 10) and linagliptin (Figure 11). In both the cases, the channel is aligned along the length of the crystal. Hence, as the crystal grows in length, the length of the channel would increase, thus increasing the distance through which solvent and water molecules would have to diffuse. The volume of channels in the crystal lattice was determined by removing all solvent molecules from the channel without disturbing the lattice framework. Spheres were then inserted into the channel to estimate the approximate diameter of the channel. In the case of imatinib mesylate, since mesylate ions are positioned in the channel, it was also removed along with the solvents for the estimation of the diameter. The channel volumes for imatinib mesylate Form-Y and linagliptin Form-I were calculated to be approximately 312.8 Å3 (channel diameter ∼4.8 Å) and 191.4 Å3 (channel diameter ∼5 Å), respectively (Figure 12). Based on atomic volume and free volume calculation, the minimum volume required to
Figure 5. Correlation between crystal sizes, estimated from SEM images, and methanol content after humidification.
Figure 6. Contour plots of methanol content (in ppm) at 40 °C as a function of relative humidity and time from humidification DoE for imatinib mesylate Form-Y: (a) fine crystals (around 5 μm) and (b) coarse crystals (around 15−30 μm).
Figure 7. Crystal structure of linagliptin Form-I with water in the channel: (a) view into the channel, and (b) view along the channel. F
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Figure 8. SEM images of the two batches of methanol solvate used for humidification DoE: (a) smaller particle sizes (∼15 μm) and (b) larger particle sizes (∼30 μm).
Initially, there are no water molecules, but as water starts to diffuse into the channel, it has to penetrate up to the center of the channel. For simplicity, the channel is approximated as a cylinder. Considering the penetration of water molecules through a cylinder, the diffusion equation can be expressed as
Table 3. Relative Contributions of Humidity, Time, and Temperature to Solvent Exchange process parameter
% contribution for small crystals
% contribution for large crystals
relative humidity time temperature
56% 32% 2%
15% 66% 2%
∂c ∂ 2c =D 2 ∂t ∂x
accommodate two molecules of each methanol, water, and mesylate ion, representing the content of one channel of imatinib Form-Y, is 291.0 Å3 (approximate channel diameter = 4.6 Å) against an available volume of 312.8 Å3. On the other hand, the minimum volume required to accommodate one methanol and ethanol, representing the content of one channel of linagliptin Form-I, is 95.5 Å3 (approximate channel diameter = 3.52 Å) against an available volume of 191.4 Å3. Moreover, mesylate ions are located in the channel of imatinib mesylate Form-Y obstructing the diffusion of solvent or water molecules through the channel (Figure 13). Hence, the diffusion of solvent or water molecules is expected to be easier and faster in linagliptin crystal compared to imatinib mesylate. The total energy of linagliptin crystal structure and individual solvent is calculated using DMol3 module of material studio 8.0, and the values are tabulated in Table S6. If we compare the total energy of the solvate/hydrate form of linagliptin with that of the corresponding desolvated/dehydrated form and calculate the binding energies of methanol/ethanol and water, it is quite evident that the water molecule is strongly bound to the channel compared to that of ethanol and methanol in Form-I. This differential binding energy provides a thermodynamic driving force for substitution of methanol/ethanol in the lattice with water. While the hydrated crystal structure for imatinib mesylate could not be solved for a similar comparison, the fact that the hydrated form of imatinib mesylate is significantly more stable than the methanol−water cosolvate indicates that water is more strongly bound in the lattice compared to methanol. 3.3.2. Estimation of Diffusion Coefficient of Solvent/Water within the Channel. The diffusion of solvent and water molecules within the channel can be approximated simply by a one-dimensional unsteady-state model of diffusion through a cylinder, as depicted in Figure 14.
where c is the concentration at time t and distance x within the cylinder, and D is the diffusion coefficient. The boundary conditions to solve this equation are c = c0 at t = 0 and c = c* at x = 0. The initial concentration, c0, can be taken as zero as there are no water molecules in the channel initially, while c* would be the maximum possible concentration within the cylinder. In the case of humidification, c* would be determined by the relative humidity that the crystal is exposed to as equilibrium would be attained when the activity of water in the lattice equals that in the vapor. The solution of the diffusion equation then leads to the following expression for concentration as a function of time, t, and penetration distance, x.14 ⎛ x ⎞ c(x) ⎟ = 1 − erf⎜ ⎝ 2 Dt ⎠ c*
Based on the DoE results, for the methanol content to fall below 3000 ppm, it takes approximately 15 h in a 5 μm crystal of imatinib mesylate exposed to 55% RH, 40 °C, while it takes about 5 h for a 30 μm crystal of linagliptin exposed to 90% RH, 30 °C. In both cases, the highest possible humidity was considered so that c* is not a limiting factor. For a 5 μm crystal of imatinib mesylate to be saturated with water molecules, the water would have to penetrate to a depth of 2.5 μm as the channel (cylinder) is open on both ends to the atmospheric concentration of c*. By fitting the diffusion coefficient to achieve c/c* = 0.95 (i.e., 95% of saturated water concentration) at x = 2.5 μm and t = 15 h, D is estimated to be 1.5 × 10−10 cm2/s for imatinib. Likewise, in the case of a 30 μm crystal of linagliptin, the penetration depth would be 15 μm. Again, fitting the diffusion coefficient to achieve c/c* = 0.95 at x = 15 μm and t = 5 h, D is estimated to be 1.5 × 10−8 cm2/s for linagliptin (Figure 15). Hence, the constriction of the channel results in a difference of about 2 orders of magnitude in the diffusion G
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Figure 9. Decrease in methanol content with time for large and small crystals at (a) 30% RH and (b) 90% RH within the temperature range of 25−40 °C.
Figure 10. (a) Predicted morphology of imatinib mesylate Form-Y wherein the channel is along the X-axis, which is along the length of the plate-like crystals. (b) SEM image shows the similarity between predicted and observed morphology.
Figure 11. Morphology prediction of linagliptin crystals, wherein the channel is aligned along the Z-axis. (a) Orientation looking into the channel. (b) Orientation looking along the channel. (c, d) SEM images showing the similarity between predicted and observed morphology.
3.4. Scalability of Solvent Exchange Processes. Solvent exchange processes that require humidification can be readily
coefficient, making the crystal size far more critical in the case of imatinib mesylate. H
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Figure 12. Spheres inserted into empty channels to estimate the channel dimensions for (a) imatinib mesylate Form-Y and (b) linagliptin Form-I.
An ANFD would require blow-through of humidified nitrogen or air, while an FBD can be programmed to operate at a particular temperature and humidity. At higher scales, FBD would be more effective due to uniform exposure of the particles to the set humidity and temperature.
4. CONCLUSION Solid-state solvent exchange has proven effective in converting pharmaceutically unacceptable or unstable solvates into commercially viable, stable hydrates or cosolvates (where the solvent content is within ICH limits). The critical process parameters controlling the solvent exchange and form transformation were identified through QbD approach for optimization. Temperature and relative humidity determined the exchange kinetics with faster solvent exchange at higher temperatures and humidity. In addition, the crystal size also played an important role in determining the extent of solvent exchange, particularly for imatinib mesylate. Molecular modeling showed the channel to be oriented along the length of the crystal; hence increase in crystal size increased the diffusion time through the channel significantly. The diffusion coefficient for imatinib mesylate was estimated to be about 2 orders of magnitude smaller than that for linagliptin as the channel was more constricted. Since the diffusion coefficient determines the rate of water penetration inside the channel, crystal size plays a much more critical role in imatinib mesylate in determining the extent of solvent exchange.
Figure 13. Constriction of the channel in imatinib mesylate due to the presence of methanesulfonic acid (MSA). Methanol and water molecules are removed to highlight the occupancy of the channel by MSA.
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Figure 14. Depiction of solvent (green) and water molecules (blue) within the channel.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00114. Single crystal parameters, structural details from powder diffraction study (SDPD), stability data, thermal characterization (DSC and TGA plots), PXRD patterns of linagliptin Form-I, and binding energy calculations (PDF)
■
Figure 15. Concentration profile of water within the channel as a function of penetration depth at various time points: (a) D = 1.5 × 10−10 cm2/s (matching the profile for imatinib mesylate) and (b) D = 1.5 × 10−8 cm2/s (matching the profile for linagliptin).
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Srividya Ramakrishnan: 0000-0002-7892-994X Sudarshan Mahapatra: 0000-0001-6369-8811 Peter W. Stephens: 0000-0002-8311-7305
scaled up with conventional drying equipment such as agitated nutsche filter dryers (ANFD) or fluidized bed dryers (FBD). I
DOI: 10.1021/acs.oprd.7b00114 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Present Addresses
Form Alpha. U.S. Patent Application Publication No. US 2008/ 0090833A1, Apr 17, 2008. (11) Sieger, P.; Kemmer, D.; Kohlbauer, P.; Nicola, T.; Renz, M. U.S. Patent Application Publication No. 2007/0259900A1, Nov 8, 2007. (12) BIOVIA Materials Studio, 17.1.0.48; Accelrys Inc.; San Diego, CA, 2017. (13) (a) Berkovitch-Yellin, Z. Toward an ab initio derivation of crystal morphology. J. Am. Chem. Soc. 1985, 107, 8239−8253. (b) Docherty, R.; Clydesdale, G.; Roberts, K. J.; Bennema, P. Applications of Bravais−Fridel−Donnay−Harker, attachment energy and Ising models to predicting and understanding the morphology of molecular crystals. J. Phys. D: Appl. Phys. 1991, 24, 89. (c) Bravais, A. Etudes Crystallographiques; Academie des Sciences: Paris, 1913. (d) Donnay, J. D. H.; Harker, D. A new law of crystal morphology extending the Law of Bravais. Am. Mineral. 1937, 22, 446−467. (e) Friedel, M. Etudes sur la loi de Bravais. Bull. Soc. Franc. Mineral. 1907, 30, 326−455. (f) The Collected Works, Vol. II; Gibbs, J. W.; Longman: New York, 1928. (g) Wulff, G. Velocity of growth and dissolution of crystal faces. Z. Krystallogr. 1901, 34, 449−530. (h) Fiorentini, V.; Methfessel, M. Extracting convergent surface energies from slab calculations. J. Phys.: Condens. Matter 1996, 8, 6525. (14) Cussler, E. L. Diffusion: Mass Transfer in Fluid Systems, 3rd ed.; Cambridge Series in Chemical Engineering; Cambridge University Press: New York, 2009.
§
S.L. Kanniah: TEVA API, Plot No. 2-G, 2-H, 2-I, Ecotech-II, Udyog Vihar, Greater Noida, India 201306. ∥ L.K. Shekhawat: IP-38, IIT Delhi Campus, Hauz Khas, New Delhi 110016, India. Notes
The authors declare no competing financial interest. CCDC 1526094, 1536700, 1536701, and 1536702 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
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ACKNOWLEDGMENTS
The authors thank the management at IPDO, Dr. Reddy’s Laboratories for supporting this work and SAIF, IIT-Chennai for single crystal data collection. Use of the National Synchrotron Light Source, Brookhaven National Laboratory was supported by the US Department of Energy, Office of Basic Energy Sciences (DE-AC02-98CH10886). Internal communication number: IPDO IPM-00531.
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ABBREVIATIONS DoE, design of experiments; MSA, methanesulfonic acid; MTBE, methyl-tert-butyl ether; RH, relative humidity; PXRD, powder X-ray diffraction; SEM, scanning electron microscope; ICH, International Council for Harmonization; QbD, quality by design
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REFERENCES
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DOI: 10.1021/acs.oprd.7b00114 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
