Generation of Hollow Crystals of a Drug with Lamellar Structure

Communication pubs.acs.org/crystal

Generation of Hollow Crystals of a Drug with Lamellar Structure Forming Ability Nallamothu Bhargavi,†,# Rahul B. Chavan,†,# and Nalini R. Shastri*,† †

Solid State Pharmaceutical Research Group (SSPRG), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India S Supporting Information *

ABSTRACT: Hollow crystals are recognized for its higher surface area, which can be exploited for improving the dissolution rate of poorly soluble drugs. To date, no reports have emerged on the hollow crystal formation ability of drugs with lamellar structure, although rolling of the lamellar structure leading to the generation of inorganic hollow crystals is a well documented mechanism. In this work, for the first time, hollow crystals of fenoprofen calcium dihydrate were prepared and characterized. These novel hollow crystals are mostly rectangular in shape with a pore diameter ranging between 2 and 25 μm as confirmed from optical microscopy and scanning electron microscopy (SEM). Powder X-ray diffraction and diffraction scanning calorimetry analysis of the recrystallized samples indicate that the drug recrystallizes without transforming into an anhydrate form. The hollow crystals demonstrated an increased dissolution rate of drug when compared to the unprocessed drug, which was attributed to their increased surface area. Similarly, unlike the plain drug, the hollow crystals have shown acceptable plastic behavior during compression studies resulting in tablets at low pressure.

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lamellar structure due to the coordination of calcium ions to fenoprofen acid. We also envisaged that hollow crystal generation of this drug might solve the dissolution13 and compressibility related issues of this drug. The crystallization experiments were carried out by both solution and antisolvent methods. Solvents used for the crystallization experiments were selected based on the drug solubility in respective solvents. Antisolvent crystallization was carried out using ethanol−isopropyl alcohol (IPA), ethanol− water, and ethanol−ethyl acetate (EA) solvent systems with ethanol as a good solvent. Two different solvent to antisolvent ratios (1:2 and 2:1) were selected for crystallization. Crystals obtained at the end of crystallization experiments were visualized under optical microscopy for the presence of hollow structure (Figure 1). A rectangular tubelike structure was clearly visualized under optical microscopy indicating hollow crystals for all recrystallized samples. However, the size and uniformity of pores in the crystals obtained from solution and antisolvent methods were different. Antisolvent methods resulted in crystals with more uniform and larger pore sizes. Among various antisolvent systems studied, ethanol/IPA and ethanol/water recrystallized systems were more uniform with smaller pore size than the ethanol/EA system. The antisolvent ratio did not affect the pore size significantly. Scanning electron

ollow crystals, also known as hollow needles, hollow whiskers, or tubular crystals, mainly result from a particular crystal growth.1 Hollow crystal formation has been studied extensively in inorganic materials such as metals and carbons. In the pharmaceutical field, hollow crystals are poorly explored and the concept is still in its infancy. Only a few active pharmaceutical ingredients (API) like dexamethasone acetate,2 carbamazepine,3 deflazacort,4 and diclofenac5 have been reported to form hollow crystals. It was well documented that crystal morphology has an impact on the performance of pharmaceutical products such as the dissolution rate, physical stability, and hygroscopicity, and processes such as compaction, filtration, drying, and storage during manufacture of the product.6−8 It is expected that the remarkable properties of hollow crystals like high specific surface area and low bulk density aid in improving many of the formulation and processing related problems.9 However, the main hurdle in generation of hollow crystals of API is that no general strategies exist, despite various mechanisms for the growth of inorganic hollow crystals are proposed.2,9,10 Recently, Feng et al. stated that inorganic molecules form hollow crystals due to rolling up of the lamellar structure to hollow pyramids.11 Up to the present date, no reports on generation of hollow crystals of pharmaceutical API which have a tendency to form a lamellar structure during crystallization are available. We have hence embarked on a project with the objective of generating hollow crystals of a thermotropic API with a lamellar structure forming tendency.12 Fenoprofen calcium dihydrate, a nonsteroidal antiinflammatory drug, was selected for the study. It forms a © XXXX American Chemical Society

Received: January 21, 2017 Revised: February 22, 2017 Published: February 27, 2017 A

DOI: 10.1021/acs.cgd.7b00099 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Communication

Figure 1. Optical images of plain drug at 50× and hollow crystals at 10× magnification: A, plain drug; B, ethanol; C, ethanol-EA; D, ethanol-IPA; E, ethanol−water.

Figure 2. SEM images of hollow crystals: A, (750×) and B, ethanol−EA (800×); C, ethanol-IPA (10×); D, (800×) and E, ethanol−water (1600×) (bracket values are magnification level).

microscopy (SEM) analysis confirmed the rectangular cross section structure of the hollow crystals (Figure 2A) with pore diameter of 2−50 μm. A closer look at the crystals (Figure 2B,C,E) indicated that the crystal surface was smooth with few fissures at the tips probably due to desolvation that may have occurred when samples were kept under vacuum for SEM analysis. Dissolution studies of plain drug and the crystallized batches were carried out using USP Type II apparatus (paddle type) in a discriminating 0.1 N HCl medium. Before performing the dissolution, crystals were passed through sieve ASTM #60 and the hollow structure integrity of the crystals was verified under microscope. The dissolution rate of the hollow crystals in comparison to that of plain drug was nearly doubled (Figure 3). Additionally, on analyzing the dissolution profiles using different drug release parameters such as % dissolution efficiency (% DE) and the amount of drug released at time 15 and 120 min,

Figure 3. Dissolution profile of plain fenoprofen calcium dihydrate and recrystallized batches: A, plain drug; B, ethanol; C, ethanol−EA; D, ethanol−IPA; E, ethanol−water.

the hollow crystals showed higher drug release compared to plain drug (Table S1). This improvement in drug release from B

DOI: 10.1021/acs.cgd.7b00099 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Communication

hollow crystals was attributed to an increased surface area due to its hollow structure. Compressibility of the drug and hollow crystals was evaluated by Well’s method. This method contains three variables (A, B, C) depending on the dwell time and the blending time. 150 mg of the sample was mixed with 1.5 mg of magnesium stearate and blended for 5 min (A); for 5 min (B) and 30 min (C). These blends were then compressed using a 8 mm die at 25 kg/cm2 for a dwell time of 2, 30, and 2 s for A, B, and C, respectively. After 24 h equilibration period, hardness of the formed compacts was determined using LABINDIA hardness tester. Elastic materials generally show capping tendency due to recoil; in such cases, A and C compacts will cap or laminate and B will maintain the integrity but forms a weak compact, whereas for plastic and fragmenting materials, the compact strength is B > A > C and A = B = C, respectively. Well’s protocol used for the study is provided in Table S2. Plain drug showed a capping tendency (Figure 4). All hollow crystals showed improved

Figure 5. PXRD pattern (top) and DSC overlay (bottom) of plain fenoprofen calcium dihydrate and recrystallized batches: A, plain drug; B, ethanol; C, ethanol−EA; D, ethanol−IPA; and E, ethanol−water.

trend in DSC, indicating that they retained the same crystalline dihydrate form even after crystallization. PXRD and DSC characterization of recrystallized samples ruled out the possibility that the generation of hollow crystals of fenoprofen calcium dihydrate was not mediated through the transformation of hydrate into anhydrate, which is one of the mechanism reported for generation of hollow crystals of organic material.14 Fenoprofen calcium dihydrate is an old drug and has been extensively studied for its thermotropic behavior.15 Crystallization techniques reported in this paper for hollow crystal generation have been used routinely, so it is rather surprising that these morphologies have not been reported before. Preliminary evidence with DSC and PXRD ruled out the possible role of dehydration of the drug during crystallization. Fenoprofen calcium dihydrate is a thermotropic drug and has the tendency to form a lamellar structure during the crystal growth stage of crystallization. We hypothesized that extrapolation of these properties for generation of hollow crystals may pave the way for improving the dissolution of drugs with a lamellar structure forming ability. Hence, there is a need to investigate

Figure 4. Results obtained from compressibility studies: A, B, and C indicate different blends as described in the text.

compressibility with higher hardness than plain drug when compressed at similar pressures. Hardness values are provided in Table S3. The crystalline nature and the absence of phase transition of the recrystallized samples were confirmed by powder X-ray diffraction (PXRD). All characteristic peaks corresponding to plain unprocessed fenoprofen calcium dihydrate were retained in the PXRD pattern of all hollow crystal batches (Figure 5) which indicate that the hollow crystals retained the same crystalline form even after crystallization experiments. Thermal characterization of samples performed using DSC revealed a single endothermic transition (onset 88 °C and peak at 110 °C) between 25 and 200 °C (Table S4), corresponding to the transition temperature of the crystalline solid into liquid crystals by losing water molecules confirming the thermotropic behavior of the drug. All recrystallized batches showed a similar C

DOI: 10.1021/acs.cgd.7b00099 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Communication

the mechanism behind the formation of hollow crystals, and determine the role of lamellar structure formation during the growth phase of crystallization.

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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.cgd.7b00099. Drug release parameters, hardness results, and DSC results of plain fenoprofen calcium dihydrate and recrystallized batches; Well’s protocol for compressibility study (PDF)

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AUTHOR INFORMATION

Corresponding Author

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

Nalini R. Shastri: 0000-0002-5246-7935 Author Contributions #

N. B. and R. B. C. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the financial support from the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Govt. of India.

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REFERENCES

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DOI: 10.1021/acs.cgd.7b00099 Cryst. Growth Des. XXXX, XXX, XXX−XXX