Polymorphisms in pharmaceutical substances are a foremost subject in drug development and formulation because differences in physicochemical properties among polymorphic forms can affect drug stability, bioavailability, and efficacy. Polymorphism is the condition in which the same substance exists in various crystalline structures, although they are chemically identical. 1 In this respect, the present work deals with the synthesis and characterization of different polymorphs of two antidepressant medicines: trimipramine maleate and clomipramine hydrochloride. Medicines are generally used to treat a range of psychiatric illnesses such as depression. These polymorphs can have a serious impact on their therapeutic effects, making it even more critical to study drug variations during development.

Earlier research on similar drugs has shown how crucial polymorphisms control drug characteristics. Ranitidine hydrochloride, a drug used in the treatment of stomach ulcers, occurs in two polymorphic forms distinguishable by sophisticated methods, such as terahertz pulsed spectroscopy (TPS). 1 In the case of venlafaxine hydrochloride, another antidepressant drug, more than one polymorph has been reported; five different forms with different characteristics and stability profiles have been detected. 2 These reports emphasize the necessity of a full study of polymorphisms in drugs used in medication, especially antidepressants such as trimipramine maleate and clomipramine hydrochloride, for optimal formulation and function.

Polymorphic forms are generally characterized using a combination of sophisticated analytical methods, including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD). 2, 3 These techniques enable an in-depth analysis of the thermal characteristics, physical properties, and crystallinity of drug substances and offer useful information regarding the potential behavior of different polymorphs under different conditions. By knowing the physicochemical characteristics of these various forms, scientists can more accurately predict their stability, solubility, and bioavailability, all of which are critical to the therapeutic effect of the drug.

The present research will contribute to the increasing amount of information regarding pharmaceutical polymorphisms, and more specifically, to trimipramine maleate and clomipramine hydrochloride. Through the synthesis and characterization of different polymorphic forms of these antidepressants, this study hopes to shed light on their physicochemical properties and stability profiles, thereby contributing to the development of better formulations. Knowledge of the polymorphic nature of these compounds will provide useful information that can have a direct influence on drug formulation, resulting in enhanced drug stability and efficacy, and ultimately better patient outcomes. The results of this research will be an important contribution to the scientific knowledge of pharmaceutical polymorphisms, assisting in the optimization of the design and delivery of these critical drugs.

Different polymorphic forms of Trimipramine Maleate and Clomipramine Hydrochloride were prepared and characterized at the R&D Laboratories of the Department of Pharmaceutical Chemistry, Krupanidhi College of Pharmacy, Bangalore, and the R & D Laboratory of R L Fine Chemicals Pvt. Ltd., Yelahanka, Bangalore. The reagents and chemicals employed in this research were of AR and LR grade and were obtained from recognized dealers such as Lancaster, Sigma, NR Chem, Rolex, and S.D.-Fine Chem. Ltd., and Merck.

The analytical methods used for the identification and characterization of the synthesized compounds and polymorphs were melting point determination, infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy ((¹H NMR and ¹³C NMR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). Melting points were measured using a Scientific MP digital instrument and IR spectra were obtained using a Fourier Transform IR Spectrophotometer. NMR spectra were obtained at the Sophisticated Analytical Instrumentation Facility, IISc, Bangalore, in deuterated chloroform for ¹H NMR and DMSO for ¹³C NMR. DSC measurements were carried out at the Society for Innovation and Development, IISc, Bangalore, on a Mettler Toledo Star System, while PXRD patterns were obtained from both IISc, Bangalore, and the STIC, Cochin University of Science & Technology, Cochin, Kerala, using Philips and Bruker AXS X-ray generators.

To synthesize Trimipramine Maleate, 10,11-dihydro-5H-dibenz[b,f]azepine was treated with sodium amide in xylene under a nitrogen atmosphere and then with N,N-dimethylamino isopropyl chloride, and the reaction was refluxed for 16 hours. The maleic acid solution was added after filtration and concentration, which led to the deposition of Trimipramine Maleate crystals. The same synthetic procedure was adopted for Clomipramine Hydrochloride with 3-chloro-10,11-dihydro-5H-dibenz[b,f]azepine and sodium amide, followed by treatment with N, N-dimethylaminopropyl chloride and refluxing.

Preparation of various polymorphs of Trimipramine Maleate (polymorphs I, II, IIIA, IIIB, IV, and V) and clomipramine hydrochloride (polymorphs IA, IB, IIA, IIB III, IV, VA, VB, and VC) was accomplished using a range of recrystallization methods. These are slow cooling, rapid cooling, and anti-solvent methods using a range of solvent combinations that are optimized according to the solubility characteristics of the compounds. The various polymorphs were recrystallized from solvents such as ethyl acetate, methanol, acetonitrile, chloroform, and IPA. Each polymorph was thoroughly characterized in terms of its melting point, IR spectra, and DSC data. The polymorphs exhibited unique thermal behaviors, as reflected by their DSC thermograms, and also had varying crystal structures and yields, with certain polymorphs yielding higher amounts than the others.

The results obtained for various polymorphs of Trimipramine Maleate are as follows.

The objective of this study was to synthesize different polymorphs of Trimipramine Maleate and Clomipramine Hydrochloride. The synthesized compounds were characterized using FTIR, NMR, and mass spectrometry. Of the various solvents and solvent combinations used for the preparation of the polymorphs, only a few regularly produced pure polymorphs. These polymorphs were characterized by FTIR, DSC, and PXRD. FTIR spectroscopy is a common and simple method for investigating and determining polymorphs. Although most molecular characteristics remain unchanged in different polymorphs, the influence of the environment on certain bonds and their vibrational properties is not always considerable enough to be significant in the IR spectra. The IR spectra of Trimipramine Maleate and its polymorphs were also investigated and compared. Trimipramine Maleate and its polymorphs (Type I, Type II, Type IIIA-IIIB, Type IV, and Type V) were found to have different IR spectral features, such as significant peak position shifts and the disappearance of certain peaks. These variations were due to the differences in the molecular structures of the polymorphs. The IR spectra of Clomipramine Hydrochloride and its polymorphs were also examined and found to have unique spectral features. Polymorphs such as Type IA-IB, IIA-IIB, and VA-VB-VC exhibited varying IR spectral features, which were ascribed to molecular-level structural differences.

Nonetheless, FTIR analysis is not considered reliable for polymorph identification. The subtlety of spectral differences can render FTIR difficult in some cases, such as when the spectral differences between polymorphs are small, or when there is more than one polymorph in a mixture. 4, 5 In these situations, other analytical methods may be required to support FTIR information for determining the identity and amount of the polymorph. Various strategies have been devised to enhance the reliability of FTIR spectroscopies. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) coupled with second-derivative analysis and peak ratio computations has been successful in the precise quantification of polymorphic mixtures. 4 Moreover, principal component analysis (PCA) of Raman spectroscopic data, which is complementary to IR spectroscopy, has demonstrated high sensitivity in the quantitative analysis of polymorphic forms. 5

DSC was also utilized to determine polymorphs, and thermodynamic information such as melting temperatures, heat of fusion, and polymorphic transformations were determined. The area of the DSC peaks was proportional to the heat absorbed or evolved during the thermal events, and the heat of fusion (enthalpy) was calculated by integrating the peak areas. For Trimipramine Maleate, DSC analysis indicated the following: Polymorph I showed a sharp endothermic peak with an onset temperature of 143.93°C, a peak at 146.70°C, and a heat of fusion of 68.06 J/g. Polymorph II showed a sharp endothermic peak at 142.22°C and a heat of fusion of 93.78 J/g. Polymorph IIIA produced a sharp endothermic peak with an onset temperature of 142.04°C and heat of fusion of 106.37 J/g, comparable to Polymorph IIIB, which produced a heat of fusion of 106.80 J/g. Polymorph IV had a greater onset temperature (146.95°C) and a heat of fusion of 55.03 J/g, whereas Polymorph V had a broad endothermic peak with an onset temperature of 142.22°C and a heat of fusion of 105.46 J/g. These differences in the melting points and heat of fusion indicate differences in the thermal behavior of the different polymorphs.

For Clomipramine Hydrochloride, DSC results were also consistent with similar trends: Polymorphs IA and IB had onset temperatures of approximately 193.82°C and 192.88°C, respectively, with heat of fusion of 112.12 J/g and 110.98 J/g. Polymorphs IIA and IIB also exhibited comparable melting points, with onset temperatures of 196.92°C and 195.51°C, respectively. Polymorph III had a slightly lower melting point (193.94°C) and heat of fusion of 108.66 J/g, whereas Polymorph IV possessed the highest heat of fusion (116.54 J/g) with an onset temperature of 194.16°C. Polymorphs VA, VB, and VC showed similar thermal characteristics, with onset temperatures of approximately 194°C and heat of fusion values of 112.52 J/g and 114.08 J/g. These differences in the melting points and heat of fusion between the polymorphs indicate differences in their molecular packing and lattice energy. The same has been observed for other drugs, such as salmeterol xinafoate, where two polymorphs (SX-I and SX-II) have different fusion enthalpies and melting behaviors 6, and for paracetamol polymorphs I and II, which have different thermal characteristics, with polymorph II converting to polymorph I before melting. 7 These thermal characteristics are important for the study of phase transitions and relative stabilities between polymorphs, as in the case of aprepitant polymorphs I and II, which show very minor differences in melting points and enthalpies of fusion. 8

PXRD was performed to study the crystalline characteristics of the polymorphs. A sharp peak in the XRD patterns revealed a crystalline character, whereas a lack of peaks indicated an amorphous nature. The relative peak intensities were computed, and the interplanar spacing was calculated using the formula nλ = 2d sinθ. The interplanar spacings of the strongest reflections of a given polymorph were compared to those of another polymorph. The differences in the PXRD diffractograms were due to the differences in the crystalline structure and molecular arrangement in the crystal lattice. For Trimipramine Maleate, the PXRD spectra indicated that polymorphs I, II, III, IV, and V differed in crystalline patterns, with Polymorphs IIIA and IIB indicating similar patterns. Likewise, for Clomipramine Hydrochloride, the PXRD spectra revealed different crystalline patterns for polymorphs I, II, III, IV, and V, with Polymorphs IA-IB, IIA-IIB, and VA-VB-VC having identical crystalline patterns. This finding is in line with the belief that polymorphs with various crystalline forms of the same substance have different X-ray diffraction patterns because of their different crystal structures. 6, 9

Notably, certain polymorphs of the two compounds shared identical PXRD patterns (IIIA-IIB for Trimipramine Maleate; IA-IB, IIA-IIB, and VA-VB-VC for Clomipramine Hydrochloride). This indicates that these groups or pairs of polymorphs have either very closely related crystal forms or packing topologies, but they differ only trivially in forms that are impossible to discern simply by PXRD. 9

This research effectively synthesized and characterized various polymorphs of Trimipramine Maleate and Clomipramine Hydrochloride employing different solvents, solvent blends, and recrystallization methods. FTIR, DSC, and PXRD analyses validated the presence of polymorphs, with IR peak shifts and heat of fusion differences observed for every polymorph. The PXRD analysis identified five polymorphs for each compound, further validating the presence of varying molecular arrangements in the crystal lattice.