Rational Crystal Polymorph Design of Olanzapine - Crystal Growth

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Rational Crystal Polymorph Design of Olanzapine Hongyuan Luo, Xuan Hao, Yanqing Gong, Jiahai Zhou, Xiao He, and Jinjin Li Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00068 • Publication Date (Web): 25 Feb 2019 Downloaded from http://pubs.acs.org on February 25, 2019

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Crystal Growth & Design

Rational Crystal Polymorph Design of Olanzapine Hongyuan Luo1, Xuan Hao2, Yanqing Gong4, Jiahai Zhou4, Xiao He2,3*, and Jinjin Li1*

1Key

laboratory for Thin Film and Microfabrication of Ministry of Education, Department of Micro/Nano-electronics, Shanghai Jiao Tong University, Shanghai 200240, China. 2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. 3 NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai, 200062, China. 4 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, 200032, Shanghai, China

*Correspondence

to: Jinjin Li ([email protected]) and Xiao He ([email protected])

ABSTRACT Polymorphism refers to the phenomenon that crystals of the same chemical composition can crystallize into several different forms with different physicochemical conditions. Studying the polymorphism of drugs has become an indispensable and important part of daily pre-design work for drug production and formulation. Here, we use ab initio computational calculations in combination with rational crystal structure design and morphology prediction to study the polymorphism of the pharmaceutical compound olanzapine, an effective drug to treat schizophrenia, using density functional theory (DFT) and second-order Møller-Plesset perturbation (MP2) methods. Different crystal polymorphs are found at the calculated energy landscape, and the analysis of Gibbs free energy and Raman spectra confirms that the long-accepted form I of 1

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olanzapine is identified as the most thermodynamically stable structure. With the increasing of temperature, the form I of olanzapine exhibits greater stability than that of form II. Rather than the traditional lattice energy calculations, we use the Gibbs free energy to evaluate the stability of crystal structure, which includes the effects of entropy and temperature and is more accurate when predicting the crystal structures. We also provide an effective method to identify different forms of polycrystalline structures based on the vibrational spectra and offers an advanced tool to predict the crystal morphologies. The present paper offers a platform for rational design of pharmaceutical molecules, which not only reestablishes the crystal structures of existing drugs but also motivate the possibility of exploration of new drugs with special efficacy.

Key words: crystal polymorphs, olanzapine, Gibbs free energy calculation, crystal structure prediction, crystal growth.

INTRODUCTION The polymorphic phenomenon of drug is that the pharmaceutical molecule can form different structures with different packing ways, which will result in different chemical and physical properties, such as solubilities, bioavailabilities, efficacies, etc1-3. The experimental searching of possible crystal polymorphs has long been a purely trialand-error test and usually take one or more years. With the increasing attention to polymorphs and the enhancement of computational power of computers, the theoretical calculation and prediction of crystal polymorphs have a tendency to replace the experimental structural searching and play an important role in drug explorations

4-5.

The development of pharmaceutical design has greatly promoted the development of crystal structure prediction (CSP), which is emerged as a complementary tool to assist pharmaceutical industries and researchers to find thermodynamically favored crystal packings with advanced efficacies

6-8.

CSP is performed via the lattice energy 2


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calculations of different crystal polymorphs and the thermodynamically stable structure is found at the bottom of the lattice energy landscape. The CSP method is widely used to search the most stable structures of pharmaceutical molecules. For example, Price and co-workers9 have performed the CSP method and found a new form of 5fluorouracil, which is a pharmaceutical molecule to treat solid tumors. The predicted new form has a lower lattice energy than the known structure and demonstrated to be the most thermodynamically stable structure. Pioneering CSP works are based on the calculations of lattice energy which neglect the effects of entropies and temperatures when evaluating the stability of crystal polymorphs. In this paper, the crystal polymorph calculations are carried out using the Gibbs free energy rather than the lattice energy, which gives the relative energetics of molecular crystals and take the entropies, temperature and polarization effects10-12 into account. Gibbs free energy calculations provide complementary chemical insights at the atomistic level and is more confident in the interpretation of experimental data. We performed the CSP method for the olanzapine molecule and generate a range of hypothetical crystal structures with low lattice energies using the MOLPAK (Molecular Packing) program9, 13, yielding many new polymorphs that correspond to the energy minimum structure. Schizophrenia is a serious chronic mental illness that can cause severe dysfunction and great pain to patients14-15. The general treatments for schizophrenia are divided into psychotherapy and physiotherapy, such as physical treatment, chemical relief, surgical operation and medicines. According to the remarkable clinical efficacy, olanzapine has become an effective medicine to treat the schizophrenia and related psychoses by affecting chemicals in the brain with lowest damage to the human’s health. Olanzapine crystallizes in 60+ crystal forms, including three anhydrates (I-III), three dihydrates (B, D, and E), and a higher hydrate16. In this work, we introduce a general ab initio computational method to calculate the Gibbs free energies and the Raman spectra of olanzapine form I and form II, and performed the crystal structure screening using the MOLPAK program, which systematically generated 1000+ densely packed structure in the common packing types. The 3



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MOLPAK program uses a rigid-body molecular structure probe to build packing arrangements and produces crude hypothetical possible crystal structures in the most common space groups. The quantum mechanical calculations demonstrated that olanzapine form I, at the bottom of Gibbs free energy landscape, is the most stable structure among the generated 1000+ forms by crystal structure screening. The calculated Raman spectrum, serving as a characteristic fingerprint, provides an effective method to identify different forms of polycrystalline structures. We further predicted the crystal shapes of olanzapine form I and form II in ethyl acetate using the spiral growth model and compares well with the experimentally observed shapes. In the present study, the crystal structure optimization is performed at the DFT level using ωB97XD/6-31G*, while the single point energy of enthalpy is further calculated at the MP2 level on the optimized crystal structure. Energy calculation with MP2 can improve the prediction accuracy and provide more reliable results. The proposed ab initio based molecular structure and intermolecular potential reproduce the crystal structures of olanzapine form I and form II. Furthermore, the molecular size of drug molecules is generally large, and the traditional ab initio method cannot be routinely applied to macromolecular systems. Therefore, we adopted the embedded fragment quantum mechanical (QM) method 17-19, dividing the internal energy per unit cell of the olanzapine crystal into a proper combination of the energies of monomers and overlapping dimers, which are embedded in the electrostatic field of the rest of the crystalline environment

20-23.

The embedding field is essential and, in our method,

consists of self-consistently determined atomic charges at the Hartree-Fock level. The embedded fragment QM method includes one-body and two-body contributions and therefore can treat the macromolecules such as pharmaceutical crystals effectively. In addition, the interaction energies between two fragments within a distance threshold are calculated by QM, while the interaction between two long-range interacting fragments is treated by charge-charge Coulomb interactions.

METHODS 4


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The Olanzapine molecule contains three fused rings (diazepine, phenyl, and thiophene) and one additional piperazine ring, with the middle seven-membered diazepine ring adopting a distorted boat conformation, as shown in Figure 124. Olanzapine(2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno-[2,3b][1,5]benzodiazepine) crystallizes in a number of solid forms, including three polymorphic nonsolvated forms (forms I, II and III), where form I and form II have clear structures while the structure of form III remains unknown due to the fact that the anhydrous form III is obtained as a mixture of polymorphs I and II25-29. Olanzapine form II can be prepared by desolvating olanzapine methanolated form I at 50ºC27, which results in the similar crystal structures of form I and form II.

Figure 1. The molecular structure of olanzapine.

The CSP of olanzapine molecules is performed by MOLPAK

13,

which is a

program that systematically generates densely packed structures and commonly used in energetic materials and pharmaceutical design. CSP can help the interpretation of conflicting experimental information. In the present study, we generate 1000+ crystal structures of olanzapine from 13 common space groups using the MOLPAK program and import them into the lattice energy landscape based on the energy sorting. The use of crystal energy landscape can provide better insights into pharmaceutical solid form characterization. We find that there are other forms closely related to form I and form II, differing only in the stacking of the same layers of olanzapine dimers, but the long5



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accepted form I, at the bottom of energy landscape, has the lowest Gibbs free energy and therefore is the most stable form of olanzapine.

Gibbs free energy calculation For the molecular crystal system, the internal energy of a unit cell can be calculated by Eq. (1) based on the embedded fragment QM approach 18, 30-33, E𝑒 =

∑𝐸

𝑖(0)

𝑖

1 + 2

+

∑ (𝐸

𝑖(0)𝑗(0)

- 𝐸𝑖(0) ― 𝐸𝑗(0))

𝑖,𝑗,𝑖 < 𝑗 𝑅𝑖𝑗 ≤ 𝜆

(1)

𝑆

∑ (1 ― 𝛿 ) ∑ (𝐸

𝑁 = ―𝑆

𝑛0

𝑖(0)𝑗(𝑛)

― 𝐸𝑖(0) ― 𝐸𝑗(𝑛)) + 𝐸𝐿𝑅

𝑖,𝑗 𝑅𝑖𝑗 ≤ 𝜆

where n is the three-integer index of a unit cell, 𝐸𝑖(𝑛) is the calculated energy of the ith molecule in the nth unit cell, and 𝐸𝑖(0)𝑗(𝑛) is the energy of the dimer for the ith molecular in the central unit cell and the jth molecular in the nth unit cell. In this work, we take a 3 × 3 × 3 supercell of the crystal(S=1). The first term of Eq. (1) gives all the monomer energy in the central unit cell. The second term gives the two-body interactions whose distance is shorter than a given cutoff distance 𝜆 in the central unit cell. λ was set to 4 Å in this study. The third term gives the interactions between two molecules with one in the central unit cell and the other one in the nth unit cell that have a shorter distance than the cutoff distance 𝜆. The first three terms of the short-range interactions are all calculated by QM in the electrostatic field of the rest crystal representing by the electrostatic potential charges fitted at the ωB97XD/6-31G* level. The long-range interaction of the dimer, in which the distance between two molecules is larger than 𝜆, are approximately treated by charge-charge Coulomb interactions. We take the background charges in the 11 × 11 × 11 supercell into account. The last term 𝐸𝐿𝑅 gives the long-range electrostatic interactions in the 41 × 41 × 41 supercell. Considering the effect of external pressure22, the enthalpy 𝐻𝑒 per unit cell can be calculated by Eq. (2): 6


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H e  Ee  PV

(2)

where P is the external pressure (here, we only consider the standard atmospheric pressure situation.) and V is the unit cell volume. For geometry optimization, the convergence criterion for the maximum force was set to 0.001 hartree/Bohr. The Gibbs free energy dependence on the temperature and pressure of a unit cell 𝐺𝑒 is calculated by Eq. (3):

Ge  H e  U v  TSv

(3)

where 𝑈𝑣 and 𝑆𝑣 are the zero-point vibrational energy and entropy per unit cell at temperature T and pressure P. For molecular crystals, the zero-point energy (ZPE) 𝑈𝑣 and the entropy 𝑆𝑣 are obtained by Eq. (4) and (5) with harmonic approximation: 1

1

𝑈𝑣 = 𝐾∑𝑛∑𝐤𝜔𝑛𝐤(2 + 1

{

𝑆𝑣 = 𝛽𝑇𝐾∑𝑛∑𝐤

𝛽𝜔𝑛𝐤 𝑒

𝛽𝜔𝑛𝐤

―1

1 𝑒

𝛽𝜔𝑛𝐤

(4)

)

―1

― ln (1 ― 𝑒 ―𝛽𝜔𝑛𝐤)

}

(5)

where 𝜔𝑛𝐤 is the frequency of the phonon in the nth phonon branch with the wave vector k, and 𝛽 = 1/𝑘0𝑇, 𝑘0 is the Boltzmann constant. The product over k must be taken over all K evenly spaced grid points of k in the reciprocal unit cell. In this study, the k-grid of 21×21×21 has been used (K=9,261). Considering the computational accuracy and time, in this work, the crystal structure optimization was performed at the ωB97XD/6-31G* level, while the single point energy of enthalpy was further calculated at the MP2/6-31G* level on the optimized crystal structure. Therefore, the calculation of He was calculated by MP2/6-31G* on the ωB97XD/6-31G* optimized crystal structure, while the 𝑈𝑣 (ZPEs) and 𝑆𝑣 (entropies) were calculated by ωB97XD/6-31G*.

Crystal morphology prediction In the 20th century, Bravais34, Friedel35, Donnay and Harker36 proposed the first model to predict the steady state crystal morphology based on the well-known FrankChernov condition as shown below37-38:

7



G1 G2 G     i . H1 H 2 Hi

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(6)

This model was named as the BFDH, where the growth rate of each crystal face Gi is proportional to the Hi (the perpendicular distance of face i from the crystal center). BFDH is a nonmechanistic method, which has been used for about 100 years although the energetics and surface chemistry effects had not been considered. The second approach to predict the crystal morphology is the attachment energy (AE) model, which enhanced the accuracy of predicting the crystal growth rates of crystal faces by taking into account the solid state interactions39-41. The AE model found it place during the 21th century for predicting the crystal morphologies, and was built into the commercial software, such as Materials Studio, and Mercury in the CCDC 42. The AE model, an improvement of the BFDH model, takes into account the attachment energy of slices, but still does not consider the influence of additives, oversaturation, solvent or other external substances43-44. Neglecting these external influences would result in the low accuracy in predicting the crystal morphologies. In the present paper, we use the spiral growth model [42-47] to predict the crystal shapes of olanzapine form I and form II and compare them with the observed experimental results. The spiral growth model, based on the mechanistic morphological theory, adequately considers the impacts of temperature, concentration, supersaturation, and other imposed growth, which can be used to perform a high-fidelity and high-precision crystal morphology prediction. In the spiral growth model, the perpendicular growth rate Gi can be expressed as45-46 Gi 

hi i hi  y i

(7)

where νi is the step velocity, y is the interstep distance, hi is the interplanar spacing, y/νi equals the spiral rotation time τi, which is given by, N

lc ,i 1 sin( i ,i 1 )

i 1

i

i  

(8)

where the angle between edge i and i+1 is αi,i+1; the critical length of edge i+1 is described as lc,i+1. The step velocity of the edge i is given by, 8


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 i  a p ,i ui i

(9)

where ui, ρi, and ap,i are the kink rate, the kink density, and the interrow distance on the ith edge, respectively. All these parameters can be found in our previous papers 47-50.

RESULTS AND DISCUSSION

Table 1. Lattice parameters of olanzapine forms I and II. Space

a

b

c

α

β

γ

V

Formula

group

(Å)

(Å)

(Å)

(deg)

(deg)

(deg)

(Å3)

Form I

C17H20N4S

P21/c

10.383

14.826

10.560

90

100.62

90

1597.77

4

Form II

C17H20N4S

P21/c

9.913

16.533

9.999

90

98.02

90

1622.74

4

The crystal structures of olanzapine form I and form II were generated based on the experimental results from the Cambridge Structural Database

51-52.

Form I has a

monoclinic unit cell with a unit cell volume of 1597.8 Å3 and a space group of P21/c, while form II have the similar crystal structure with form I. Table 1 shows the lattice parameters of olanzapine form I and form II.

9


Z


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Figure 2. Crystal structures of olanzapine form I (left) and form II (right). The molecules are colored by the symmetry operation.

Figure 2 shows the crystal structures of olanzapine form I and form II, where the molecular arrangement of form I in the unit cell is significantly different from that of form II. Rajni et al.53 have simply tested the lattice energy of different forms of olanzapine, where they speculated that form I, having the lowest energy, is the most stable structure by roughly ranking the lattice energy. Here, we reproduce Rajni et al.’s work based on the Gibbs free energy (rather than the lattice energy) calculations at the DFT and MP2 levels with high accuracy and predicted 1000+ different forms of olanzapine using the MOLPAK program. We confirm Rajni et al.53’s work and demonstrate that the long-accepted structure of form I, at the bottom of the Gibbs free energy landscape, has the lowest free energy among different olanzapine forms.

Table 2. Structural parameters of olanzapine forms I and II from experiment and ωB97XD/6-31G* optimization (DFT), respectively. Parameters

Expt. Form I

DFT Form I

Expt. Form II

DFT Form II

a/Å

10.383

10.056

9.913

9.737

b/Å

14.826

14.702

16.533

16.399

c/Å

10.560

10.426

9.999

9.861

Table 2 shows the lattice constants’ comparison of olanzapine forms I and II at room temperature and standard atmospheric pressure, where the optimized lattice constants are in good agreement with the experimental values. The lattice constant deviation between the experiment and calculation is 0.33 Å for a of form I and others are within 0.2 Å.

Gibbs free energy calculations Figure 3 shows the Gibbs free energy difference per primitive unit cell between 10


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olanzapine form II and form I (form II energy minus form I energy), where the single point energy of enthalpy is calculated at the MP2/6-31G* level based on the ωB97XD/6-31G* optimized crystal structures, and the ZPEs and entropies were calculated by ωB97XD/6-31G*. Figure 3 shows that the Gibbs free energy of form I is always lower than form II and the structure of olanzapine form I is more stable than from II. In Figure 3, the Gibbs free energy difference increases with the increase of temperature, indicating that the stability of form I becomes more obvious with the increase of temperature. Specifically, the Gibbs free energy difference per unit cell between form II and form I is about 11 kJ/mol at 5 K and increases to 19 kJ/mol at 350 K.

Figure 3. The calculated Gibbs free energy differences per primitive unit cell between form II and form I (form II-form I) from 5 to 350 K at the standard atmospheric pressure, where the single point energy was calculated at the MP2/6-31G* level based on the ωB97XD/6-31G* optimized crystal structures, and the ZPEs and entropies were calculated by ωB97XD/6-31G*.

Vibrational Spectra The vibrational spectrum serves as a fingerprint to identify the crystal structure of the molecule22, 54. Here, we use the Raman spectrum to investigate the different forms 11



Page 12 of 25

of olanzapine molecules. Figures 4 and 5 are the calculated Raman spectra of olanzapine form I and form II, along with the experimental data. The calculations were performed at the ωB97XD/ 6-31G* level, while the observed Raman spectra were taken from Ref.

53.

Figures 4 and 5 show that our calculation accurately reproduced the

Raman peaks for both forms, where the red and green curves are the calculated Raman spectra for olanzapine form I and form II, and the blue and yellow curves are the observed Raman spectra for olanzapine form I and form II, respectively. In Figure 4, there are six and three notable observed Raman peaks in middle-frequency (Figure 4(a)) and high-frequency (Figure 4 (b)) regions of olanzapine form I, respectively. Specifically, the observed characteristic peaks, locating at 890 cm-1 and 970 cm-1 in Figure 4(a) and 2750 cm-1, 2910 cm-1, and 3040 cm-1 in Figure 4(b) of olanzapine form I, are well reproduced by our calculation. Figure 5 shows the calculated Raman spectra of olanzapine form II at middle-frequency and high-frequency regions, which also match the experimental results very well. The scale factor was fitted to 0.945 for the high frequency regions (> 2300 cm-1, the scale factor was not applied for the frequency region below that).

Figure 4. The calculated (red curves) and observed (blue curves)[13] Raman spectra of olanzapine form I at 298 K and under standard atmospheric pressure.

12


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Figure 5. The calculated (green curves) and observed (yellow curves)[13] Raman spectra of olanzapine form II at 298 K and under standard atmospheric pressure.

Figure 6. Raman spectrum comparison of olanzapine form I (red curves) and form II (green curves) at 298 K and under standard atmospheric pressure. The characteristic peaks are boxed with black rectangles.

We compare the Raman spectra of olanzapine from I and form II in Figure 6, where the characteristic Raman peaks considered as fingerprints are obtained to discriminate the olanzapine form I from form II. In the black box of Figure 6(a), there are four Raman peaks for form II and three Raman peaks for form I, respectively, and therefore the one more peak locating at the 1020 cm-1 is the characteristic peak for form II. In the same way, the Raman peak at 3040 cm-1 in Figure 6(b) is the characteristic peak of olanzapine form I. Form Figure 6, one can distinguish form I and form II of olanzapine crystals 13



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from these characteristic Raman peaks, which provides an effective way to identify different forms of polycrystalline structures.

Crystal structure screening Figure 3 show that the Gibbs free energy of form I is always lower than that of form II. However, is there any other form of olanzapine crystal that has a lower Gibbs free energy than form I? To resolve this issue, we generate 1000+ possible crystal structures from the 13 common space groups using the MOLPAK program13. According to the energy sorting, we select 8 candidates from 2 different space groups, who have the lowest lattice energies and locate at the bottom of energy landscape. Table 3 shows the optimized lattice parameters for the 8 predicted structures by the MOLPAK program, along with the experimental lattice constants of form I and form II of olanzapine. All crystal structures were optimized at the ωB97XD/6-31G* level. Figure 7 shows the calculations of Gibbs free energy difference per primitive unit cell between the 8 predicted structures, the form II and the form I by the MOLPAK program, where the long-accepted form I still locates at the bottom of Gibbs free energy landscape, and the Ola128 is the closest structure to form I.

Table 3. Optimized lattice parameters for the 8 predicted structures from MOLPAK, as well as the experimental data of form I and form II of olanzapine crystals. Structure ID

Space group

a(Å)

b(Å)

c(Å)

α(deg)

β(deg)

γ(deg)

Form I

P21/c

10.383

14.826

10.560

90

100.62

90

Form II

P21/c

9.913

16.532

9.999

90

98.02

90

Ola 36

P21/c

6.291

24.635

11.760

90

115.36

90

Ola 94

P21/c

16.824

6.107

19.092

90

61.64

90

Ola 115

P21/c

6.173

34.077

10.056

90

92.47

90

Ola 128

P212121

16.436

16.156

6.214

90

90

90

Ola 144

P21/c

8.147

32.097

7.233

90

76.89

90

Ola 152

P21/c

9.167

10.872

18.485

90

101.37

90 14


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Ola 166

P212121

9.301

28.096

6.611

90

90

90

Ola 192

P21/c

21.628

6.057

22.208

90

43.5

90

Figure 7. The calculated Gibbs free energies difference per primitive unit cell of form I, form II and 8 predicted structures (using the MOLPAK program) of olanzapine crystals from 5 to 350 K.

The Gibbs free energy landscape of the molecular crystal is an important tool for interpreting the range of experimental solid forms as well as in predicting possible structures that have yet to be crystallized. Using the structures of 8 predicted candidates and form II and comparing them with form I of give discrete points in Figure 8, which shows the Gibbs free energy as a function of root-mean-square deviation (RMSD, in Å) of the 8 predicted structures, and form II of olanzapine crystals with reference to the form I structure. The crystal free energy landscape shows that there are alternative, probably metastable structures of olanzapine crystals, but the long-accepted form I has the lowest Gibbs free energy among all structures. In general, the larger the RMSD, the higher the Gibbs free energy of the olanzapine crystal.

15



Page 16 of 25

Figure 8. The Gibbs free energy differences per primitive unit cell of the predicted and observed olanzapine structures with the reference of form I, as a function of unit cell root-mean-square deviation (RMSD) in Å.

Crystal shape prediction It is well known that crystal morphology (e.g., shape, size) can significantly affects the final use of solid products (e.g., bioavailability of pharmaceutical compounds, catalytic activity), and the downstream performance of the entire process by influencing the filtration and drying times49, 55-56. Therefore, the general method for predicting and improving crystal morphology would serve as a major breakthrough for product and process design. Different polymorphisms would result in the same or different crystal morphologies, which can seriously affect the physicochemical characteristics of drug molecules and produce different efficacies. Rational design and control of the crystal morphologies of polymorphism play an important role in pharmaceutical manufactures and other practical applications. Various models have been proposed by pioneers to predict the crystal shapes of pharmaceuticals in the literatures [31-38]. Comparing with 16


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the non-mechanistic model (such as BFDH and AE models), the mechanistic spiral growth model, including the effects of dynamics and additives, is regarded as one of the most accurate and efficient methods to predict the crystal morphology of pharmaceuticals. However it requires significant expertise to use and each new system studied typically requires additional investigation 57-59. The details of the spiral growth model can be found in the METHODS Section and our previous review article49.

Figure 9. The predicted and observed shapes of olanzapine form I and form II.

Figure 9 shows the predicted and observed shapes of olanzapine form I grown from ethyl acetate and form II. The observed shapes of olanzapine form I were prepared in ethanol, where the stirred suspension was heated to 70 ºC to dissolve the solids, then the solution was cooled down to ambient temperature. Olanzapine form I was formed after three days of stilling-culture. The sample of olanzapine form II was prepared by desolvating olanzapine ethanolate at 50ºC 27. As shown in Figure 9, the predicted crystal shapes of olanzapine form I (a) and form II (c) are in excellent agreement with the experiments. Moreover, Figure 9 shows that different forms of pharmaceutical 17



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molecules would have the similar crystal morphology, but they could exhibit different stabilities, bioavailabilities and result in different efficacies. Therefore, rational design of polymorphism by studying their energies, spectra and morphologies would provide an efficient and fast polycrystalline structural identification for crystallographers and pharmaceutical industries, which can greatly shorten the drug development time, reduce the cost and accelerate the time-to market of new drugs, and eventually bring huge economic benefits for the society.

CONCLUSIONS In this work, based on the embedded fragment QM method, we introduce the DFT and MP2 theories to the computational study of different forms of olanzapine crystal, which can be used to identify the most stable crystal structure and determine the characteristic vibrational spectra of different polymorphs. The present theoretical study accurately reproduced the lattice parameters and Raman spectra of olanzapine form I and from II. The crystal structure screening, performed by the MOLPAK program, further confirms that the long-accepted form I is the most stable crystal structure of olanzapine especially at the higher temperature. The characteristic peaks in Raman spectra offer an effective way to discriminate different polymorphs. We further investigate the morphologies of olanzapine form I and form II, and the predicted crystal shapes based on the spiral growth model agree well with the experiments. The development of improved theoretical approach for accurate Gibbs free energy landscape calculation, the crystal morphology prediction, as well as the characteristic Raman spectrum identification provide an accurate and efficient platform for the pharmaceutical structure prediction and design.

AUTHOR INFORMATION Corresponding Authors *(J.L.) E-mail: [email protected] 18


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*(X.H.) E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS: The authors are grateful for the financial support provided by the National Natural Science Foundation of China (Nos. 51672176, 21673074, and 21761132022), the National Key R&D Program of China (Grant No. 2016YFA0501700), the Intergovernmental International Scientific and Technological Cooperation of Shanghai (No. 17520710200), Shanghai Municipal Natural Science Foundation (Grant No. 18ZR1412600), and Young Top-Notch Talent Support Program of Shanghai, and NYU-ECNU Center for Computational Chemistry at NYU Shanghai. We thank the Supercomputer Center of East China Normal University for providing us computational time. We also thank Prof. Michael F. Doherty from the University of California at Santa Barbara for his support and guidance.

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"For Table of Contents Use Only"

Title: "Rational Crystal Polymorph Design of Olanzapine" Author(s): Luo, Hongyuan; Hao, Xuan; Gong, Yanqing; Zhou, Jiahai; He, Xiao; Li, Jinjin TOC graphic:

Synopsis: The comparison of Gibbs free energy differences between predicted and observed olanzapine structures with the reference of form I.

25


Rational Crystal Polymorph Design of Olanzapine - Crystal Growth

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