*1.5.6.3 Angle of repose*

The angle of repose depicts a solid's ability to flow. It is a quality that has to do with how difficult it is for particles to move around one another. The surface of the powder or granule pile can only be angled away from the horizontal plane at this maximum angle.

$$\tan \theta = \mathbf{h} / \,\mathrm{r}.\tag{3}$$

$$\theta \doteq \tan^{-1} \ln \text{/r.} \tag{4}$$

where θ= angle of repose, h = height of heap, r = radius of base of heap circle. *Modification of Physicochemical Properties of Active Pharmaceutical Ingredient… DOI: http://dx.doi.org/10.5772/intechopen.110129*

Method: The fix funnel method was used to calculate the angle of repose. A funnel was positioned 2–4 cm above the platform. The sample powder was gradually pushed through the funnel until the tip of the cone of sample powder that was created barely touched the stem. The height of the sample powder cone and the radius of the powder heap's circular base were then measured in order to estimate the angle of repose.

#### *1.5.6.4 Compressibility index and Hausner's ratio*

Compressibility index and the closely related Hausner's ratio have recently emerged as the most straightforward, quick and well-liked techniques for forecasting powder flow characteristics. Because all of these factors can affect the compressibility value, the compressibility index has been projected as an indirect evaluation of size and shape, surface area, bulk density, moisture content and cohesiveness of materials. By measuring the bulk density and the tapped density of crystals, the compressibility index and Hausner's ratio are estimated [68].

' Compressibility Index = Tapped density – Bulk density / Tapped density ×100.Hausner s ratio = Tapped density / Bulk density.

#### *1.5.7 Tabletability*

The crystal packing, tabletability and compaction, which are crucial factors during preformulation research, can be impacted by the co-crystallization of the drug and coformer. Co-crystals of paracetamol with trimethylglycine and oxalic acid were found to have better compaction behaviour than pure drug [38]. The formation of co-crystals with 4-aminobenzamide and isoniazid improved resveratrol's tabletability. Comparing co-crystals to conformers or pure drugs, tabletability of co-crystals was higher [24]. Co-crystallization allowed for the modification of the mechanical properties of APIs, and it demonstrated higher tabletability for vanillin isomer co-crystals than for isomers and conformer [29].

#### *1.5.8 Dissolution studies*

The dissolution study is a crucial tool for figuring out the drug's bioavailability. The dissolution test is used to determine whether an API is soluble. Dissolution studies are used to calculate the rate of drug release over time in the dissolution medium and forecast how well the formulation will work *in vivo*. The dissolution apparatus can be used to conduct dissolution studies for co-crystals. The appropriate dissolution medium is described in the drug protocol of the referred pharmacopoeia, and it can be used to conduct the dissolution studies for the co-crystals. The drug samples can be gathered in the right amount at the right time and can be examined using the right tools, like HPLC or UV [69, 70].

#### *1.5.9 Stability*

Stability study is extremely important during the development of new dosage formulation. During the development of pharmaceutical co-crystals, several stability studies should be performed such as relative humidity stress, chemical stability, thermal stability, solution stability and photostability study. In relative humidity stress, automated water sorption/desorption studies are performed to determine the effect

of water on the formulation. Several researchers studied the behaviour of co-crystals under relative humidity stress conditions [71–73].

#### **1.6 Case study of multicomponent co-crystals and drug-drug co-crystals**

Fael H et al. have prepared co-crystal of norfloxacin-based solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, whereas the co-crystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher [74]. Machado Cruz et al. develop a new co-crystal of the poorly water-soluble antifungal agent itraconazole. The co-crystal is stable in aqueous solution, and comparison with previously described itraconazole co-crystals revealed a relationship between the coformer's solubility and the intrinsic and powder dissolution rates. Analyses of the physical co-crystal and common excipient mixtures' dissolution behaviour were also conducted [75].

Nugrahani et al. prepared the mono- and tetrahydrate of the salt co-crystal diclofenac sodium-l-proline. Single-crystal X-ray analysis was used to characterize the hydrates, which were found to have higher solubilities and dissolution rates than the sodium salt of diclofenac acid and the anhydrous diclofenac acid-l-proline co-crystal. The salt co-crystal dissociated into a physical mixture of diclofenac acid and L-proline as a result of the release of water during drying. It is interesting that this process can be reversed. Diclofenac sodium-L-proline tetrahydrate was restored when the dried sample was maintained at 72% relative humidity and 25°C [76].

Kale et al. studied co-crystallization on the tabletability of rivaroxaban and found an improved tabletability for rivaroxaban-malonic acid. The crystal packing, specifically the presence or absence of slip planes, slip plan topology, the degree of intermolecular interactions and d-spacing, could be used to explain the tabletability of alonic acid and rivaroxaban combined with malonic acid. Slip planes with zigzag and flat-layered topologies are both present in rivaroxaban. This study's findings on the relationships between crystal structure and mechanical properties shed light on the deformation of crystals with multiple slip-plane systems [77].

Jiaxin PI et al. prepared baicalein (BE) is one of the main active flavonoids representing the variety of pharmacological effects including anticancer, anti-inflammatory and cardiovascular protective activities, but it is very low solubility, dissolution rate and poor oral absorption limit the therapeutic applications. In this study, a nano-co-crystal approach was successfully used to increase the bioavailability and dissolution rate of BE. High-pressure homogenization was used to create baicalein-nicotinamide (BE-NCT) nano-co-crystals, which were then tested both *in vitro* and *in vivo*. BE-NCT has formed the new solid phase as co-crystals, as shown by physical characterization results from scanning electron microscopy, dynamic light scattering, powder X-ray diffraction and differential scanning calorimetry [78]. Latif et al. synthesized paracetamol co-crystals to improve compaction or tabletability of paracetamol. The author created a co-crystal of paracetamol using caffeine as a conformer using techniques such as dry grinding, liquid-assisted grinding, solvent evaporation and anti-solvent addition. He then observed that the paracetamol's mechanical properties and compaction power have increased [79]. Iyan et al. developed simvastatin-nicotinamide co-crystals by solvent evaporation to improve the solubility of simvastatin by co-crystallization using nicotinamide as co-crystal agent or co-former and evaluated for solubility. When compared to raw simvastatin, saturated solubility of the co-crystal increased threefold, according to the observation [80]. Shubhangi et al. synthesized co-crystals of poorly water-soluble drug darunavir. It is a BCS Class II medication with a poor solubility. Succinic acid was

#### *Modification of Physicochemical Properties of Active Pharmaceutical Ingredient… DOI: http://dx.doi.org/10.5772/intechopen.110129*

used as a conformer during the cooling crystallization process that produced co crystals. By dissolving an excess amount of co-crystals in water for 24 hours on a rotary shaker and measuring the saturation solubility with a spectrophotometer, the author was able to determine the aqueous solubility of darunavir. This technique resulted in 1.92-fold increases in saturation solubility [81]. Prabhakar et al. also prepared co-crystal of piroxicam and studied for solubility. Author used various conformers such as adipic acid, benzoic acid, cinnamic acid, citric acid, glutaric acid, phydroxybenzoic acid, hippuric acid, malonic acid, resorcinol, 6 saccharine sodium, 1-hydroxy-2-napthoic acid, sodium acetate, urea, catechol, ferulic acid, aerosil-200, nicotinamide, para amino benzoic acid, anthranilic acid and succinic acid for synthesis of co-crystals and performed saturated aqueous solubility of co-crystal and found significant increase in solubility of drug after formulating as co-crystals [82]. Zheng et al. synthesized co-crystals of resveratrol with conformers 4 aminobenzamide and isoniazid and studied its enhanced solubility and tabletability. Author observed that tabletability of RES is poor and because of this even at high pressure that is 0.6 MPa and lamination of tablets, while tablets are prepared with co-crystals of resveratrol-4-aminobenzamide, and tensile strength more than 3 MPa is attained at 250 MPa compaction pressure. Author concluded that co-crystal formation improved tabletability of drug. Co-crystals of paracetamol with trimethylglycine and oxalic acid were found to have better compaction behaviour than the drug alone. The formation of co-crystals with 4-aminobenzamide and isoniazid improved resveratrol's tabletability. The tabletability of co-crystals was higher than that of coformers or pure drugs. Co-crystallization allowed for the alteration of the mechanical properties of APIs, and co-crystals of the vanillin isomers with the same coformer demonstrated greater tabletability than the isomers and conformer [65]. Muddukrishna et al. studied synthesis of paclitaxel and naringen co-crystal to improve solubility by solvent-assisted grinding method. The drug paclitaxel (PTX), which belongs to class IV, has a low solubility in water. Shake flask method was used to study the solubility of paclitaxel and naringen co-crystal for 72 hours at room temperature. HPLC analysis of the samples revealed 2.4-fold increases in the saturation solubility [83]. Pinky et al. formulated co-crystal tablet dosage form of clarithromycin to enhance the bioavailability. As clarithromycin is BCS Class II drug author prepared co-crystals by using urea as conformer by solvent evaporation method, and developed tablet formulation and evaluated for solubility, dissolution and bioavailability studies. Author concluded that the formulated tablets of clarithromycin co-crystals showed improved solubility and *in vitro* drug release profile as compared to Marketed Tablet, and thereby increase oral bioavailability and therapeutic effect [84]. Mounika et al. prepared co-crystals of fexofenadine. According to the BCS classification, fexofenadine belongs to the class II of drugs because of its high permeability and low solubility, which acts as rate-limiting factors in achieving the desired bioavailability. Therefore, by evaporating solvent, the author created co-crystals of fexofenadine using tartaric acid as a co-former, and they found that 7 of them had a higher drug release than the formulation [85]. Carmen Almansa et al. identified cocrystal of tramadol hydrochloride-celecoxib, a brand-new active pharmaceutical ingredient (API)-API co-crystal with favourable physicochemical and dissolution properties that result from the intrinsic 1:1 molecular ratio of rac-tramadol HCl and celecoxib. A medical need that is frequently met by combination therapy is the adequate treatment of pain. In comparison with individual APIs or their combination, API-API co-crystals represent a new strategy that has the potential to enhance physicochemical properties, bioavailability, stability or formulation capacity. This could result in improved pharmacokinetic profiles and clinical benefits. The single-crystal X-ray diffraction structure of ctc revealed a supramolecular 3D network in which the two

active enantiomers of tramadol and celecoxib are connected by hydrogen bonds and chloride ions. Ctc also displayed a clearly defined differential scanning calorimetry profile. The saturation effect for highly insoluble celecoxib occurred at a higher concentration in ctc than in celecoxib alone, according to oversaturation studies. Celecoxib and tramadol were released from ctc more quickly and more slowly than they were from the individual APIs, respectively, according to comparative intrinsic dissolution rate studies, which suggested that ctc would have better pharmacokinetic behaviour. These data support the clinical development of ctc for the treatment of pain along with those from preclinical studies [86]. Shivarani Eesam et al. prepared drug-drug co-crystal of carvedilol with hydrochlorothiazide: A significant challenge in the discovery and development of new drugs is increasing the hydrophilicity of poorly water-soluble drugs. One method for improving the hydrophilicity of such drugs is co-crystallization. Carvedilol (CAR), a non-selective beta/alpha1 blocker with poor aqueous solubility and high permeability, is categorized as BCS class II and is used to treat mild-to-moderate congestive heart failure and hypertension. The goal of this work is to increase the solubility of CAR by creating co-crystals using the diuretic hydrochlorothiazide (HCT) as a coformer. Slurry conversion was used to create CAR-HCT (2: 0.5) co-crystals, which were then analysed using DSC, PXRD, FTIR Raman and SEM. The co-crystals were the subject of solubility, stability and dissolution (*in vitro*) studies [87]. Kang Zheng et al. presented study reports on the MNZ-PYR co-crystal, a new co-crystal of the antimicrobial drug metronidazole (MNZ) that uses pyrogallol (PYR) as a co-crystal former. Utilizing single-crystal X-ray diffraction, infrared spectroscopy, thermal analysis and density functional theory calculations, the crystal structure of the MNZ-PYR co-crystal is investigated. Due to the high-energy conformer of PYR in the co-crystal's crystal lattice, the MNZ-PYR co-crystal exhibits a higher dissolution rate than MNZ. The colour of the MNZ-PYR co-crystal changes from white (raw MNZ and PYR) to yellow as it forms, and this theoretical interpretation is based on calculations using time-dependent density functional theory. UV-vis spectroscopy is used to characterize this colour change. The findings point to the potential use of the co-crystal strategy for API colour tuning, providing opportunities for formulation development [88]. Braham Dutt et al. create aspirin (AN) and benzoic acid (BZ) co-crystal by using the solvent evaporation technique. CSD (Cambridge Structure Database) software and ΔpKa value method were used for the choice of the drug and coformer and for prediction of CC formation. Differential scanning calorimetry, Fourier transformation infrared spectroscopy and X-ray diffraction methods were used for the analysis of CCs. A total of 24 Wistar rats divided into four groups participated in *in vivo* anti-inflammatory studies [89]. Bwalya A. Witika et al. prepared co-crystal of zidovudine (AZT) and lamivudine (3TC) that are antiviral agents used orally to manage HIV/AIDS infection. The development and production of 3TC and AZT nanocrystals were carried out using a pseudo one-solvent bottom-up methodology. Rapid injections of AZT in methanol and 3TC in de-ionized water were combined with sonication at 4°C in a vessel that had been pre-cooled. A Zetasizer was used to characterize the resulting suspensions. The Zeta potential, polydispersity index and particle size were clarified. Powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy were all used for further characterization. The stability of the nano co-crystals and the production of nano co-crystals with particular and desirable critical quality attributes (CQA), such as particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30 mV, were evaluated for various surfactants. In the nanometer range, co-crystals were produced by all surfactants. When sodium dodecyl sulphate was used in the process, only ZP was within specification,

### *Modification of Physicochemical Properties of Active Pharmaceutical Ingredient… DOI: http://dx.doi.org/10.5772/intechopen.110129*

whereas the PDI and PS are concentration-dependent for all nano co-crystals produced [90]. Dnyaneshwar P. Kale et al. presented purpose of this work is to comprehend the crystallographic underpinnings of the mechanical behaviour of rivaroxaban-malonic acid co-crystal (RIV-MAL Co) in comparison with its parent constituents, rivaroxaban (RIV) and malonic acid (MAL). By performing "out of die" bulk compaction and nanoindentation, the mechanical behaviour was assessed at both the bulk and particle levels. MAL < RIV < RIV-MAL Co was the order of tabletability for the three solids. Despite having a reasonably strong bonding strength, MAL demonstrated "lower" tabletability due to its lower plasticity (BS). This behaviour was influenced by the absence of a slip plane and "intermediate" BS. The different surface topologies of the slip planes were primarily blamed for RIV's "intermediate" tabletability. While the corrugated topology of secondary slip planes (1, 0, 2) may adversely affect the plasticity, the presence of a primary slip plane (0, 1, 1) with flat-layered topology may favour the plastic deformation of RIV. Additionally, RIV crystal's tabletability was aided by its higher elastic recovery. RIV-MAL Co′s significantly "higher" tabletability compared to the other two molecular solids was caused by its greater plasticity and BS. The higher degree of intermolecular interactions, the larger separation between adjacent crystallographic layers and flat-layered topology slip across the (0, 0, 1) plane all helped RIV-MAL Co. exhibit better mechanical behaviour. It is interesting to note that the relationship between a particle level deformation parameter and a bulk-level deformation parameter, H/E (i.e. the ratio of mechanical hardness H to elastic modulus E), was found to be inverse (i.e. tensile strength at zero porosity). The co-crystal crystallographic properties of materials were highlighted in this study as having a positive impact on tabletability [91]. Ilma Nugrahani et al. prepared zwitterionic co-crystal of L-proline and diclofenac acid. This multicomponent crystal's solubility, though, was still inferior to that of diclofenac sodium salt. In order to determine whether a multicomponent crystal of diclofenac sodium hydrate could be produced using the same coformer, L-proline, which was anticipated to enhance the pharmaceutics performance, screening, solid phase characterization, structure elucidation, stability and *in vitro* pharmaceutical performance tests were among the methods used. In order to determine the molar ratio of the multicomponent crystal formation, a phase diagram screen was first performed. The single crystals were then created by slowly evaporating the material under two different conditions, yielding two different forms: one was shaped like a rod, and the other was like a flat square. The formation of the new phases was confirmed by the characterization using infrared spectroscopy, thermal analysis and diffractometry. The new salt cocrystals were finally solved structurally as stable diclofenac-sodium-proline-water (1:1:1:4) and unstable diclofenac-sodium-proline-water (1:1:1:1), known as NDPT (natrium diclofenac proline tetrahydrate) and NDPM, respectively (natrium, diclofenac, proline monohydrate). These multicomponent crystals had better solubility and dissolution rates than diclofenac sodium by itself. According to the experimental findings, this salt co-crystal can be developed further [92]. Xavier Bull et al. identified and prepared 13 co-crystals of nefiracetam, a poor water-soluble nootropic compound. The co-crystallization agents citric acid, oxalic acid and zinc chloride were used to produce three of them. The stability, solubility and rate of dissolution of the latter have all undergone thorough structural and physical characterization, and they have been compared to the original Active Pharmaceutical Ingredient (API) [93]. Prafulla P. Apshingekar et al. prepared co-crystal by ultrasound, which is known to affect crystallization; consequently, using a slurry co-crystallization method, the impact of high-power ultrasound on the ternary phase diagram has been thoroughly investigated. To comprehend how the accelerated circumstances during ultrasound-assisted co-crystallization will impact

various areas of the ternary phase diagram, a thorough investigation was conducted. The ternary phase diagram was significantly affected by the use of ultrasound, especially in the regions where the co-crystals of caffeine and maleic acid were 2:1 and 1:1 (which narrowed). Additionally, the solution region was expanded in the presence of ultrasound, while the stability regions for pure caffeine and maleic acid in water were contracted. Maleic acid and caffeine solubility as well as the stability of co-crystal forms in water were found to be related to the observed effect of ultrasound on the phase diagram [94]. Dwi Setyawan et al. analysed the physicochemical characteristics and *in vitro* dissolution profile of co-crystals of quercetin and malonic acid made by solvent-drop grinding. Using the solvent-drop grinding method and 20% (w/v) ethanol addition, quercetin (Q ) and malonic acid (MA) were co-crystallized in the molar ratios of 1:1 (CC1) and 1:2 (CC2) in a shaker mill that was run for 30 minutes. Differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM) and Fourier transform infrared (FT-IR) spectroscopy were used to identify the co-crystal phase. The paddle method was used to perform *in vitro* dissolution at 100 revolutions per minute in a medium of citrate buffer (pH 5.0 ± 0.05) containing 2.0% (w/v) sodium lauryl sulphate at 37 ± 0.5°C [95]. Agnes Nuniek Winantari et al. prepare and characterize co-crystals of acyclovir through co-crystallization of acyclovir-succinic acid (AS) for the purpose of enhancing the drug's physical properties. Using the solvent evaporation method, AS co-crystals were created. By using the polarization microscope, scanning electron microscopy (SEM), differential scanning calorimetry, powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy, the co-crystals were characterized [96]. Jose Lopez-Cedrun et al. prepared co-crystal of tramadol–celecoxib (CTC), containing equimolar quantities of the active pharmaceutical ingredients (APIs) tramadol and celecoxib (100 mg CTC = 44 mg *rac*–tramadol hydrochloride and 56 mg celecoxib), which is a novel API-API co-crystal for the treatment of pain. In order to effectively treat acute pain following oral surgery, we sought to determine the CTC dosage. Nine Spanish hospitals participated in a phase II dose-finding, double-blind, randomized, placebo- and active-controlled study (EudraCT number: 2011-002778-21) on male and female patients under the age of≥18 who were experiencing moderate-tosevere pain after having two or more impacted third molars that required bone removal extracted. A computer-generated list was used to randomly assign eligible patients to receive one of six single-dose treatments (CTC 50, 100, 150, 200 mg; tramadol 100 mg; and placebo). The sum of pain intensity difference (SPID) over 8 hours as measured in the per-protocol population was the main efficacy endpoint [97]. Muhammad Inam et al. designed two new co-crystals, nicotinamide and ticagrelor, have been prepared with improved solubility. An innovative co-crystallization technique has been developed to increase ticagrelor's solubility because it has a low solubility and a high rate of dissolution. This technique uses a structurally homogenous crystalline material, an active pharmaceutical ingredient (API) and co-former indefinite stoichiometric amount. A 1:1 co-crystal of ticagrelor (TICA) and nicotinamide (NCA) was created and characterized using FTIR, DSC and XRD. TICA-NCA hydrate's single-crystal structure was also examined. When compared to the solubility of a free drug, the solubility of co-crystals was investigated in pH 2 acidic medium, which was a significant improvement. Co-crystal had a higher *in vitro* dissolution rate than the commercial product [98]. Heinrich Buschmann et al. invented co-crystals of duloxetine and co-crystal formers selected from active agents preferably with analgesic activity, processes for preparation of the same and their uses as medicaments or in pharmaceutical formulations, more particularly for the treatment of pain [99]. Carlos Ramon Plata Salaman et al. invented a co-crystal of celecoxib and venlafaxine, methods for making it and its use as medications

### *Modification of Physicochemical Properties of Active Pharmaceutical Ingredient… DOI: http://dx.doi.org/10.5772/intechopen.110129*

or in pharmaceutical formulations, more particularly for the treatment of pain, including chronic pain, or of depression in patients who suffer from chronic pain and/or chronic inflammation, or in patients with a chronic musculoskeletal inflammatory illness, with the inflammatory illness preferably being chosen from osteoarthritis or rheumatoid arthritis [100]. Prabhakar Panzade et al. prepared, formulated and evaluated the co-crystal of piroxicam by testing various coformers. Piroxicam co-crystals were created using the dry grinding method. The crystalline phase's melting point and solubility were established. DSC, IR and XRPD were used to characterize the potential co-crystal. Evaluations were also conducted on solubility and dissolution rate, two additional pharmaceutical properties. Piroxicam co-crystal orodispersible tablets were created, improved upon and tested using a 32 factorial design [101]. Mirela Nicolo et al. prepared co-crystal of betulinic acid and ascorbic acid. It has been shown that betulinic acid (BA) is a very effective anticancer agent against a variety of tumour cell lines, including those from the breast, colon, lung and brain. Betulinic acid has a strong cytotoxic effect but has a low water solubility, which is reflected in its low bioavailability. Co-crystallization emerged as a promising strategy among the many tactics used to enhance its physicochemical and pharmacokinetic profile in order to address these drawbacks. Thus, the goal of our research was to create BA and ascorbic acid co-crystals (BA+VitC) in isopropyl alcohol using a hydrothermal process. SEM, DSC, XRPD and FT-IR spectroscopy were used to characterize the newly formed co-crystals, showing that BA+VitC co-crystals were formed, and their antioxidant activity showed an additive antioxidant effect. BA+VitC co-crystals were tested on a variety of cell lines, including HeLa (cervical cancer), MCF7 and MDA-MB-231 (human breast cancer), B164A5 and B16F0 (murine melanoma), and immortalized human keratinocytes (HaCat). Results of BA on the examined tumour cell lines after co-crystallization with vitamin C showed a superior cytotoxic effect while maintaining a good selectivity index, most likely as a result of an improved BA water solubility and consequently an optimized bioavailability [102]. Abdolati Ali Mohamed Alwati et al. developed a new method for co-crystal preparation, which adhered to green chemistry principles, and provided advantages over conventional methods. It was decided that the best technology to achieve these goals was a brand-new, solvent-free, high-power ultrasound (US) technique for creating cocrystals from binary systems. Ibuprofen nicotinamide (IBU-NIC), carbamazepinenicotinamide (CBZNIC) and carbamazepine-saccharin (CBZ-SAC) co-crystals were investigated for the use of this technology for solid-state co-crystal preparation [103].
