International Journal of Drug Development and Research

Keywords

Lomefloxacin, dissolution rates, cocrystals, product development

INTRODUCTION

Improvement of API physicochemical and biopharmaceutical properties as well as in vivo performance and, hence, are a potential new alternative in the selection of optimal solid forms in drug product development1, 2. Traditionally, co- crystal screening has been based on empirical methods such as solvent evaporation, crystallization from melts, and grinding3, 6.

The improvement of the physicochemical properties of active pharmaceutical ingredients (APIs) has become a major concern in the pharmaceutical industry. Both branded and generic pharmaceutical companies spend considerable efforts and resources on the discovery of new crystalline forms of their APIs. This intense research has been driven by the need for improving undesirable properties of APIs witnessed in the commercialization pipelines7, 8. APIs are complex chemical structures with functional groups that may take part in the molecular recognition events. It is the presence of these functional groups, such as amides and carboxylic acids that provides inability to engage in supramolecular event with the co crystal formers that show complementary hydrogen bond donor and acceptorsites8.

Pharmaceutical co crystals, a recent addition to the class of crystalline solids, are generating increasing interest, and offer an alternative means of improving the physicochemical properties of an API9-11. Cocrystallisation offers several key advantages: (1) co crystals are crystalline with definite stoichiometry, leading to better solid-state stability and more predictable physical properties and performance than amorphous solids; (2) co crystal design involves altering hydrogen bonding motifs rather than making or breaking covalent bonds, thus retaining the safety and pharmacological profiles of the drug molecule; (3) co crystals of all types of APIs(weakly acidic or basic or non-ionisable) can in principle be prepared, in contrast to salt formation technology; (4) greater diversity is possible with co crystal solid forms because of the availability of numerous coformers (food additives, preservatives, pharmaceutical excipients, and other APIs); (5) co crystals offer patenting opportunities because they are new solid forms of APIs; (6) co crystals can be generated using green production technologies such as grinding.

Lomefloxacin HCL is a bactericidal fluoroquinolone agent with activity against a wide range of gramnegative and gram-positive organisms. The bactericidal action of lomefloxacin HCl results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. The elimination half-life was approximately 8 hours. There was no drug accumulation with singledaily dosing in patients with normal renal function. Pharmaceutical co crystals can be prepared by several methods such as mechanochemical or traditional solution crystallization methods approaches. The uses of reaction crystallization methods, thermal microscopy and differential scanning calorimetric methods have also been reported. The mechanochemical methods such as grinding may be ideal for co crystal screening. Grinding and solution crystallization methods are widely used for co crystal screening purpose. These methods differ primarily by the amount of liquid used and means to convert a given amount of starting components into crystals12-13.

The API under consideration in the current work is Lomefloxacin HCl no published reports on the crystal structure and solid state characterization of solid not reported.

MATERIALS AND METHODS

Materials:

Lomefloxacin HCl was received as a gift sample from the Simpex Pharma Pvt. Ltd., Uttarakhand, India. Other chemicals and solvents were obtained from different commercial suppliers.

Preparation of Lomefloxacin -Salicylic acid co crystals:

Lomefloxacin-salicylic acids were prepared at various molar ratios by kneading method using motar and pestle for 30 min to obtain the co crystals.

Preliminary Characterization:

The melting point of samples was determined by melting point apparatus.

Fourier transforms infrared spectroscopy:

Infrared spectra of the pure lomefloxacin HCl, Lome- SA and Lome-Urea were recorded using a IR 230 spectrophotometer (Shimadzu). In the range of 650- 4000cm-1with KBr pellets.

Differential scanning calorimetry:

Thermal analysis of the samples was performed on a DSC Q1000 (TA Instruments) which was calibrated for temperature and enthalpy using indium. Samples (3-5 mg) were crimped in non-hermetic aluminum pans and scanned from 30 to 200 oC at a heating rate of 10oC/min under a continuously purged dry nitrogen atmosphere (flow rate 50mL/min).The instrument was equipped with a refrigerated cooling system. The data were collected in triplicate for each sample.

Powder X-ray diffraction:

The solid phases obtained from the stability and solubility experiments were analyzed by PXRD, and the resulting diffraction patterns were compared with the diffraction patterns of pure phases. The patterns were collected ona Siemens DIFFRAC plus 5000 powder diffractometer with CuKradiation (1.54056 A°). The tube voltage and amperage were set at40 kV and 40mA, respectively. The divergence slit and antiscattering slit settings were variable for illumination on the 20 mm area on the sample. Each sample was scanned with2θ between 5oand 60 o with a step size of 0.02 o and 0.5 s at each step. The sample stage was spunat 30 rpm. The instrument was precalibrated using a silicon standard.

RESULTS AND DISCUSSION

In the present study, the co grinding method was used to prepare the co crystal because mechanochemical technology was shown to be available to the pharmaceutical field and be friendlier to the environment than the solvent method. When there was LomefloxacinHCl co grinding with the salicylic acid at a molar ratio of 1:1 for 30 min, In addition to salicylic acid, the co crystal formation of Lomefloxacin HCl with other carboxylic acids such as maleic acid, glutaric acid and malonic acid was investigated.

The physicochemical properties of Lomefloxacin HCl, salicylic acid, urea at a molar ratio of 1:1 were investigated by other solid state analytical methods. The molecular interaction between lomefloxacin HCl and salicylic acid was examined by FTIR spectroscopy. All the spectra of the lomefloxacin HCl and its co crystals with urea, salicylic acid and oxalic acid are depicted in (Fig.2, 3, 4, 5.).

Co crystalline phase characterization and identification of cocrystalstudied using differential scanning calorimetry (DSC). DSC data is presented for the lomefloxacin HCl and its co crystals with urea, salicylic acid and oxalic acid only (Figs.6, 7, 8, 9) and powder X-ray diffraction (PXRD). PXRD data is presented for the lomefloxacin HCl and its co crystals with urea, salicylic acid and oxalic acid only(Fig.10, 11, 12, 13).

The standard curve of lomefloxacin HCl in methanol (Table 3 and Figure 1), it was observed that the drug obeys beer Lambert’s law in concentration range 1- 5μg/ml. The melting point of the obtained drug sample was found to be 2850C, which is within the reported value of 290- 3000C. It complies with official standards thus indicating the purity of the drug sample (Table 2). Lomefloxacin HCl was analyzed by FTIR spectral analysis for identification of the pure drug. From the spectra, it was concluded that there was no interference in the functional group as the principal peaks of the lomefloxacin HCl were found to be unaltered. The FTIR spectrum of lomefloxacin HCl and in combination with the urea, salicylic acid and oxalic acid is shown in Figure 2, 3, 4 and 5.Differential Scanning Calorimetry (DSC) can be used to investigate and predict the changes in crystalline form of the drug. Polymorphism is the capability of a substance to crystallize into two or more different crystalline forms. Any crystalline changes in the drug may change its melting point, bioavailability, and drug release kinetics. The crystalline change in the drug lomefloxacin HCl was studied using differential scanning calorimetry (DSC) by testing the melting characteristics of the drug. Figure 6, 7, 8 and 9compares the DSC thermo gram of lomefloxacin HCl and its mixture with urea, salicylic acid and oxalic acid.

Preliminary characterization of 1:1 and 1:2 Co crystals:

The DSC thermograms and pXRD analysis strongly suggests the formation of a new co crystalline form. Our current efforts in generating pure co crystals of this new phase and a follow-up single crystal X-ray study should confirm this true nature of this physicochemical. The physicochemical properties of lomefloxacin HCl, urea, salicylic acid and oxalic acid at a molar ratio of 1:1 were investigated by other solid state.

CONCLUSIONS

Co crystals of API were produced using co grinding method and a new co crystalline form of LOME-SA was unveiled. GRIND method revealed to be a suitable method. This study demonstrates the ability of producing co crystals of several APIs, confirming the potential of co grindings as alternative methods to produce pharmaceutical co crystals. Further work is currently in progress towards a thorough characterization of this new LOME-SA co crystal and analysis of its physicochemical properties. The physicochemical properties such as solubility and dissolution rate of this complex will be further investigated. An extensive study about the control of co crystal stoichiometry using novel SCF and Spray drying techniques with kinetic and thermodynamic aspects of co crystals formation will be addressed in a future work.

ACKNOWLEDGEMENT

We are very grateful to the vice-chancellor and registrar of KLE University and also would like to thank all staff of KLE university college of Pharmacy, Belgaum for providing constant support and enthusiasm to carry out this work.

Tables at a glance

Table 1 Table 2 Table 3

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13

References

1. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties.Cryst. Growth Des 2009; 9(6): 2950-2967.
2. Jung MS et al. Bioavailability of indomethacin-saccharin cocrystals.J Pharm Pharmacol2010; 62(11): 1560-1568.
3. Vishweshwar P et al. Pharmaceutical cocrystals. J Pharm Sci 2006; 95(3): 499-516.
4. Trask AV, Jones W. Crystal engineering of organic cocrystals by the solid-state grinding approach. Top CurrChem 2005; 41–70.
5. Berry D, Seaton C, Clegg W, Harrington R, Coles S, Horton P, Hursthouse M, Storey R, Jones W, Friscic T.Cryst. Growth Des. 2008; (8), 1697–1712.
6. Basavoju S et al.Indomethacin–saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization.Pharm Res 2008; 25(3): 530-541.
7. BrittainH. Polymorphism in Pharmaceutical Solids.New York: Marcel Dekker, Inc., 1999.
8. Vishweshwar P et al. Pharmaceutical cocrystals. J Pharm Sci2006; (95): 499-516.
9. Jones W et al. Pharmaceutical cocrystals: an emerging approachto physical property enhancement. MRS Bull2006; 31: 875-879.
10. Schultheiss N, Newman A. Pharmaceutical cocrystals and theirphysicochemical properties. Cryst Growth Des2009; 9(6): 2950-2967.
11. Trask AV, Jones W. Achievingpolymorphic and stoichiometric diversity in cocrysatal formation: importance of solid state grinding, powder x-ray structure determination seeding, Cryst.Growth Des. 9(20009) 1106-1123.
12. Vishweshwar P et al. Synthesis and structural characterization of cocrystal and pharmaceutical cocrystals: mechanochemitstry vs. slow evaporation from solutionCryst. Growth Des. 9(2009) 1106-1123.