Properties Of Active Pharmaceutical Ingredients Research Articles

Preparation, characterization and antimicrobial assessment of selected ciprofloxacin salts.

The formation of salts is considered a simple strategy to modify the physicochemical properties of active pharmaceutical ingredients. In this study, seven novel binary and ternary organic salts of ciprofloxacin (CP) were prepared with benzoic acid (BA), acetylsalicylic acid (ASA), p-coumaric acid (PCMA) and p-aminosalicylic acid (PASA). They were characterized by spectroscopic techniques and differential scanning calorimetry. Solubility and partition coefficients values were also measured. Evaluation of the antimicrobial activity of the organic salts against Staphylococcus aureus and Staphylococcus epidermidis revealed that most of the new salts had higher antimicrobial activity than CPHCl against both strains. The most active compounds against S. epidermidis and S. aureus were CP-PASA and CPPCMA, resp., which were up to fourteen times more potent than parent CP-HCl. Our findings indicated a strong correlation between the lipophilicity of the formed salts and their antimicrobial activity and showed that an optimum value of lipophilicity (log P = 0.75) seemed to be necessary to maximize the antimicrobial activity. These findings highlighted the improved physical, thermal and antimicrobial properties of the new salts of CP that can aid in providing higher bioavailability than CP-HCl.

Cocrystal Formulations: Evaluation of the Impact of Excipients on Dissolution by Molecular Simulation and Experimental Approaches

Cocrystallization has matured into an established technique for fine-tuning the physicochemical properties of active pharmaceutical ingredients (APIs). This technique has been adopted by pharmaceutical drug companies, with increasing numbers of cocrystal-based drug products now entering the market. Surprisingly, however, studies into the formulation aspects of cocrystal-based drugs are relatively few and far between compared to the vast literature on their design, synthesis, and characterization. We herein report the results of our investigations into cocrystal–excipient interactions in water that determine the dissolution properties of cocrystals in formulation by a combination of molecular dynamics (MD) simulation and experimental approaches. Two cocrystals of an antirheumatic drug, leflunomide (LEF) with 3-hydroxybenzoic acid (HBA) and 2-picolinic acid (PIC), were assessed in formulation with the frequently used excipients lactose and dibasic calcium phosphate (DCP). For comparison, the dissolution of neat LEF formulations with these excipients was also evaluated. The parameters deduced from MD simulations, such as solvent-accessible surface area, intermolecular hydrogen bonds among formulation ingredients and water, and interaction energy between the API (or cocrystal) and water were found to be essential indicators in the prediction of cocrystal formulation dissolution trends. It was found that the presence of lactose as an excipient improved the dissolution of the cocrystal formulation compared to the neat cocrystals, most notably for the LEF-PIC cocrystal. In contrast, DCP was seen to have a detrimental effect on the dissolution of cocrystal formulations, all exhibiting lower dissolution than their neat cocrystal counterparts and LEF. Careful analysis of these results revealed that the nature of the excipient plays a significant role in the dissolution properties. While the improved dissolution of the lactose formulations was attributed to its hydrophilic nature, the ionic and hydrophobic nature of DCP was likely responsible for its detrimental effect. The results of the MD simulations were found to be in excellent agreement with the experimentally observed dissolution hierarchy.

The Challenge for Engineering Pharmaceutical Crystalline Solids: Scientific and Regulatory Affairs Perspectives for Crystal Structure Design and Prediction

The Breakthrough into solid-state research has become emerging approach for structure determination of Active Pharmaceutical Ingredients (APIs) and excipeents that consequently influence their physic-chemical properties, biopharmaceutical and pharmacokinetic profiles. The concept of conventional pharmaceutical salts has been extended to multicomponent crystals which diversity in nature of the non-covalent intermolecular interactions determine the crystal packing patterns within the structures, and thus modulate the native properties of APIs. Therefore, the aim of this review is to highlight how accomplishments in crystallographic research on molecular crystal have influenced their classification and how these new solid phases have been recognized by the regulatory bodies. The advantage to explore the pharmaceutical crystalline solids of one API implies the selection of the form with favorable properties for the development of formulations for pharmaceutical dosage forms.

Solvent dependent 4-aminosalicylic acid-sulfamethazine co-crystal polymorph control

Despite polymorphism of crystalline active pharmaceutical ingredients (APIs) being a common phenomenon, reports on polymorphic co-crystals are limited. As polymorphism can vastly affect API properties, controlling polymorph generation is crucial. Control of the polymorph nucleation through the use of different solvents during solution crystallization has been used to obtain a desirable crystal polymorph. There have been two reported polymorphic forms of the 4-aminosalicylic acid-sulfamethazine co-crystals. These forms were found to have different thermodynamic stabilities. However, the control of co-crystal polymorph generation using preparation parameter manipulation has never been reported. The aim of this study was to establish the effect of different solvent parameters on the formation of different co-crystal polymorphic forms. Selection of the solvents was based on Hansen Solubility Parameters (HSPs) as solvents with different solubility parameters are likely to interact differently with APIs, ultimately affecting co-crystallization. Eight solvents with different HSPs were used to prepare co-crystals by solvent evaporation at two different temperatures. Through characterization of the co-crystals, a new polymorph has been obtained. The hydrogen bond acceptability seemed to affect the co-crystal form obtained more than the hydrogen bond donation ability. Furthermore, the use of HSPs can be utilized as an easy calculation method in screening and design of co-crystals.

Biocompatible Ionic Liquid Enhances Transdermal Antigen Peptide Delivery and Preventive Vaccination Effect.

Ionic liquids (ILs) attract significant attention as novel solvents for drug delivery systems because of their ability to solubilize poorly soluble drugs and tune the physiological properties of active pharmaceutical ingredients. For the next generation of IL-based drug delivery systems, biocompatibility is a high priority. In the current study, choline-fatty acids ([Cho][FA]) were used as a biocompatible IL to mediate the dissolution of a water-soluble antigen peptide in an oil-based skin penetration enhancer. Among the candidate fatty acids (C8, C10, C12, C14, C16, C18:0, and C18:1), C18:1 was selected because of its low cytotoxicity and mediation of skin permeability for an antigen peptide. Using IL[Cho][C18:1] and an oil-based penetration enhancer, the flux of transdermal delivery of the peptide increased 28-fold compared with delivery using an aqueous vehicle. Furthermore, the IL-mediated transcutaneous vaccination succeeded in suppressing tumor growth in vivo compared to injection. The skin irritation produced by this formulation was tested using an in vitro 3D constructed skin tissue model and an in vivo histological study, which concluded that the formulation did not cause skin irritation. The results suggest that biocompatible IL-mediated dissolution in an oil-based skin penetration enhancer is a promising strategy for transdermal drug delivery.

Vibrational spectral and structural characterization of multicomponent ternary co-crystal formation within acetazolamide, nicotinamide and 2-pyridone.

Ternary co-crystal, as a novel co-crystal design strategy developed on the basis of binary co-crystal, could be used to improve the physicochemical properties of active pharmaceutical ingredients (APIs) efficiently. However, it is difficult to obtain specific ternary co-crystals since such ternary one involves complex assembly of three different molecules. There are few reports on the micro-molecular structure respect of specific ternary co-crystal systems. In present work, 1:1:1 ternary co-crystal between acetazolamide (ACZ), nicotinamide (NAM) and 2-pyridone (2HP) has been synthesized successfully by mechanical grinding approach, and their structures are investigated by terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy combined with theoretical calculation at the molecular level. The experimental THz spectral results showed that ACZ-NAM-2HP ternary co-crystal and the starting parent materials exhibited a few distinct spectral features in frequency-domain absorption spectra. Likewise, the Raman spectral result also shows some difference between the co-crystal and starting raw materials. Through density functional theory (DFT) calculations, the theoretical THz/Raman spectra and vibrational modes of two kind of possible ternary co-crystal theoretical forms (form I and II) between ACZ, NAM and 2HP were obtained. By comparing experimental and theoretical spectral results, the most suitable structure and vibrational modes of ACZ-NAM-2HP ternary co-crystal were determined. These results provide a wealth of information and unique method for studying molecular assembly and also inter-molecular interactions in specific ternary co-crystals at the molecular level in the emerging pharmaceutical co-crystal fields.

Nano Co-crystal Engineering Technique to Enhance the Solubility of Ezetimibe

Background: Co-crystals have been highly promising for tailoring physicochemical properties of Active pharmaceutical ingredient (API) by coupling with co-former. Objectives: The objective of the present work was to prepare and characterize novel nano co-crystals of Ezetimibe by different methods in various ratios of co-formers and to optimize the formulation based on the enhancement in solubility and dissolution rate. Methods: Ezetimibe nano co-crystals were prepared employing oxalic acid, succinic acid and maleic acid as co-formers by solvent evaporation method and anti-solvent method. Results: Instrumental analysis of co-crystals (DSC, IR, SEM and XRD) was performed to characterize the novel nano co-crystals. Dissolution studies and chemical stability were assessed and compared with pure Ezetimibe. The formulation with maleic acid as a co-former in the molar ratio of Ezetimibe and maleic acid (0.4:0.4) was found to be efficient than oxalic acid and succinic acid. The co-crystal dissolution profile in distilled water containing 0.5% SLS showed 18.8 folds increase in the dissolution efficiency and was found to be 95.2% within 45 min. Conclusion: The results demonstrate feasibility of co-crystallization method using maleic acid as co-former to enhance the solubility of poorly soluble drug Ezetimibe. Key words: Anti-solvent, Co-Formers, Maleic Acid, Oxalic acid, Solubility, Solvent evaporation, Succinic acid.

Concurrent Antisolvent Electrospraying: A Novel Continuous Crystallization Technique

Pharmaceutical co-crystals (CCs) are multicomponent materials that enable the development of novel therapeutic products by enhancing the properties of active pharmaceutical ingredients, such as solubility, permeability and bioavailability. Currently, CCs are a commercial reality; nonetheless, their industrial production remains a challenge due to problems related to scale up, control and mode of preparation, which usually relies on batch production rather than continuous. This paper describes the implementation of a concurrent coaxial antisolvent electrospray (Co-E), as a new manufacturing technique, for the synthesis of CCs in a rapid, continuous and controlled manner. The features of Co-E were sized against other co-crystallization methods such as antisolvent crystallization, neat and liquid assisted grinding. Three pairs of amino acids were used as model compounds to demonstrate the features of this new system. The Co-E displayed exclusive product characteristics, including spherical particle morphology and enhanced CC formation. This technique exhibited robustness against process disturbances, displaying consistent product characteristics. Co-E represents a new alternative for the reliable production of CCs and other pharmaceutical products.

Enhancement of Solubility BCS Class II and IV Pharmaceuticals by Liqusolid Technique: A review

Many techniques can be used to improve drug solubility, which is the development of the liquisolid technique. This technique has a mechanism for increasing the surface area of the drug as well as wetting from the addition of non-volatile solvents resulting in a lower surface tension and contact angle, so the solubility and drug release very increases. Liquisolid tablets show a lower contact angle compared to the conventional tablets. The liquisolid technique approach is also promising because the process is simple in making low production costs and allows the manufacturing industry, including non-volatile solvents, fillers, dryers, and disintegrants. Liquisolid characterized by specific instruments such as powder x-ray diffraction (PXRD), Fourier transforms infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscope (SEM). Several liquisolid techniques are described in this review. The liquisolid technique is proven and able to change the physicochemical properties of active pharmaceutical ingredients, especially the solubility, drug release, and stability of the formula so that this technique can be a solution for class II and IV BCS pharmaceutical active drug classes.Keywords: Active Pharmaceutical Ingredients, Contact Angle, Solubility, Drug Release, Stability, Liquisolid Technique

Comparison of statistical methods for predicting penetration capacity of drugs into human breast milk using physicochemical, pharmacokinetic and chromatographic descriptors

ABSTRACT In silico methods are often used for predicting pharmacokinetic properties of drugs due to their simplicity and cost-effectiveness. This study evaluates the penetration of 83 active pharmaceutical ingredients into human breast milk with an experimental milk-to-plasma ratio (M/P) obtained from the literature. Multiple linear regression (MLR), partial least squares (PLS) and random forest (RF) regression methods were compared to uncover the relationship between physicochemical, pharmacokinetic and membrane crossing properties of active pharmaceutical ingredients (APIs) using their rapid reference measurement value (Rf values), thin-layer chromatography (TLC) data from albumin-impregnated plates. Molecular descriptors of APIs proven to be important for their crossing into breast milk, including protein binding, ionisation state and lipophilicity and TLC data, have been included in the development of the prediction models. The best regression results were achieved by MLR (r 2 = 0.83 and r 2 = 0.86, n = 28) and RF (r 2 = 0.85, n = 58). In addition, the discriminant function analysis (DFA) was performed on acidic, basic and neutral drugs separately and showed a prediction accuracy of 93%, with M/P included as the discriminating variable.

Role of stable hydrogen isotope variations in water for drug dissolution managing

Abstract In the present work, we provide the results of defining by utilizing Laser diffraction spectroscopy, the kinetic isotopic effect of solvent and constant of dissolution rate κ, s−1 of аn active pharmaceutical ingredient (API) in water with a different content of a stable 2 1 H _2^1{\rm{H}} isotope on the basis of the laws of first-order kinetics. This approach is based on the analysis of the light scattering profile that occurs when the particles of the dispersion phase in the aquatic environment are covered with a collimated laser beam. For the first time, the dependence of the rate of dissolution is demonstrated not only on the properties of the pharmaceutical substance itself (water solubility mg/ml, octanol–water partition coefficient log P oct/water, topological polar surface area, Abraham solvation parameters, the lattice type), but also on the properties of the solvent, depending on the content of stable hydrogen isotope. We show that the rate constant of dissolution of a sparingly hydrophobic substance moxifloxacin hydrochloride (MF · HCl) in the Mili-Q water is: k=1.20±0.14∙10−2 s−1 at 293.15 K, while in deuterium depleted water, it is k=4.24±0.4∙10−2 s−1. Consequently, we have established the development of the normal kinetic isotopic effect (kH/kD >1) of the solvent. This effect can be explained both by the positions of the difference in the vibrational energy of zero levels in the initial and transition states, and from the position of water clusters giving volumetric effects of salvation, depending on the ratio D/H. The study of kinetic isotopic effects is a method that gives an indication of the mechanism of reactions and the nature of the transition state. The effect of increasing the dissolution of the API, as a function of the D/H ratio, we have discovered, can be used in the chemical and pharmaceutical industries in the study of API properties and in the drug production through improvement in soluble and pharmacokinetic characteristics.

The Influence of Deuterium on the Properties of Pharmaceutical Substances (Review)

Introduction. The study discusses the hydrogen isotope 2 H effect on the biological activity of pharmaceutical substances.Text. Two aspects of the deuterium effect on the properties of active pharmaceutical ingredients and excipients are considered. The first one involves the use of deuterated substances, new compounds or substituted counterparts. Replacing protium with deuterium is used to reduce the rate of biotransformation. The kinetic isotope effect (KIE), expressed in a decrease in the rate of biotransformation as a result of deuteration, allows us to predict the rapid development of new directions in the development of pharmaceuticals. With the same therapeutic effect, an improvement in pharmacokinetic characteristics, a decrease in toxicity, a blocking of the epimerization of optically active substances, a change in the mechanisms of action are observed. The second aspect of the deuterium effect is associated with an increase in KIE of known pharmaceutical substances in aqueous solutions with a deuterium/protium ratio (D/H) lower than in natural water. For the first time, dose-response diagrams for deuterium demonstrate identity with essential microelements. There is a safety zone for the certain D/H relationship, beyond which the organism's vitality decreases. Improved kinetic characteristics are demonstrated for molecular level and for biological objects of various hierarchical levels. In particular, they include the possibility of increasing the dissolution rate of substances, the influence on the processes of mutarotation and the optical activity of chiral substances, the degree of accumulation of necessary elements in medicinal plants, and other processes.Conclusion. The results make it possible to predict the mechanisms of deuterium influence on the biochemical transformations of pharmaceutical substances in the body.

The effect of polymorphism on active pharmaceutical ingredients: A review

Active pharmaceutical ingredients (API) are the main components in the production process of pharmaceutical products. If the API has a good quality, then it will lead to good pharmaceutical products. API consists of more than one different crystal form which, then forms a polymorph through the process of polymorphism. Until now, API polymorphism is still a big challenge in the pharmaceutical industry. That is because the nature of polymorphism is difficult to predict. One of them is by crystallizing molecules in one or many crystalline forms or combining with other molecules to form stable co-crystal. This process will lead to several polymorph forms of one certain API. Sometimes, these forms will have characteristics that differ one to another. Each polymorph has different mechanical, physical, thermal, and chemical properties that will affect the solubility, dissolution, bioavailability, stability, bioequivalence, and manufacturing of the API. Therefore to know the nature of an API, it is necessary to characterize the polymorphic form of the API before. If the form is not incompatible with the formulation, it can cause a failure in the production process. This review will discuss the effect of polymorphism on the physicochemical properties of API. It is hoped that this review can become the basis for improving the stability and effectiveness of pharmaceutical products.

Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach.

The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion‐corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol−1) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher‐order molecular ICCs with functional properties.

Benzodiazepines co-crystals screening using FTIR and Raman spectroscopy supported by differential scanning calorimetry.

Co-crystals, which are defined as "solids that are crystalline materials composed of two or more molecules in the same crystal lattice" have recently been the focus of increased interest in the pharmaceutical industry since co-crystallization can improve unfavorable physicochemical properties of active pharmaceutical ingredients. Thus, the quest for new co-crystal screening methods has become an issue of importance. The aim of this work was, therefore, to show to what extent expanded methodology based on FTIR and Raman spectroscopy supported by the DSC method can be used as a reliable tool to screen co-crystallization. Because co-crystals of benzodiazepines had not yet been obtained, a set of 72 binary mixtures composed of eight 1,4-benzodiazepine derivatives and nine coformers were used as model substances. Potential co-crystals were prepared in solid-state by liquid-assisted grinding procedure. The characteristic FTIR and Raman bands which reflect hydrogen bond formation between benzodiazepine and coformer were used as proof of co-crystal creation. DSC was used as a supporting tool to reflect the phase transitions which occur during co-crystallization. As a result of the study, four potential co-crystals can be selected: lorazepam with nicotinamide, chlordiazepoxide with p-aminobenzoic and saccharin, and estazolam with fumaric acid. The detailed spectral and thermal characteristics of these systems are presented in this work. Thus, the proposed methodology of co-crystal screening based on FTIR and Raman data supported by the DSC examination of phase transitions facilitates the screening and detection of benzodiazepine co-crystal prepared by short time components ground with a slight additional volume of solvent.

Cocrystal formulations: A case study of topical formulations consisting of ferulic acid cocrystals

Renaissance of cocrystals as alternative solid forms for fine-tuning physicochemical properties of active pharmaceutical ingredients (APIs) has paved way for development of marketable cocrystals. The current literature reveals established strategies for the design, synthesis and characterization of cocrystals. However, barring a few isolated case studies, strategies for development of cocrystal formulations have been underdeveloped. Herein we report topical formulations of an antioxidant, ferulic acid (FA), which contain the active in its cocrystal form. Cocrystals of FA with the coformers relevant to skin care such as urea, nicotinamide (NA) and isonicotinamide (INA) have been prepared and oleogel formulations of these have been developed. The cocrystal with urea and an anhydrous cocrystal with INA have been identified for the first time in this study. The novel cocrystals were structurally characterized by single crystal X-ray diffraction. Solubility and stability studies have revealed higher solubility of the cocrystals with NA and INA than the parent active and greater stability of FA in formulations that contained the cocrystals with INA and urea than the corresponding formulations containing physical mixtures or parent active. In vitro membrane permeation tests have ascertained sustained release profile of active from the formulation that contained the FA•INA cocrystal. The higher solubility, greater stability and sustained active release profile of the FA•INA cocrystal formulation make it a promising topical formulation of FA.

Study on Development of Exploring Method and Evaluation for Cocrystals to Improve Physicochemical Properties of Active Pharmaceutical Ingredients

Study on Development of Exploring Method and Evaluation for Cocrystals to Improve Physicochemical Properties of Active Pharmaceutical Ingredients

Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity.

Co-crystallization is a phenomenon widely employed to enhance the physio-chemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methyl-ideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of co-crystals of exemestane with thio-urea by liquid-assisted grinding. The purity and homogeneity of the exemestane-thio-urea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N-H⋯O hydrogen bonding between the amine (NH2) groups of thio-urea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC50 = 3.86 ± 0.31 µg ml-1) compared with the API (exemestane), which was found to be inactive, and the co-former (thio-urea) (IC50 = 21.0 ± 1.25 µg ml-1), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of co-crystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.

Cocrystallization: An innovative route toward better medication

Nowadays, poor solubility, lower bioavailability, and hindered physical, chemical, and biopharmaceutical properties of active pharmaceutical ingredients (APIs) become a very important matter of discussion for pharmaceutical scientists. It is a challenging task for pharmaceutical researchers and industry to develop a suitable formulation with improved physicochemical properties. The process of cocrystallization is long known; however, in the recent times, this approach has gained enormous importance in pharmaceuticals as a relatively new method for enhancement of solubility, bioavailability, stability, thermal properties, permeability, tablet ability, and other related physicochemical properties. Cocrystals are multicomponent systems in which two components, an API and a coformer, were present in stoichiometric ratio and bonded together with non-covalent interactions in the crystal lattice. Cocrystallization offers better optimization of not only physicochemical properties but also therapeutic response and pharmacological properties of APIs. The design of a cocrystallization experiment is based on robustness, hydrogen bonding rules, and potential intermolecular interactions. Various theoretical and experimental approaches increase the chances for selection of a suitable coformer, the most challenging step during the design of cocrystal formation. The present review covers classification of cocrystals, drug selection criteria for cocrystals, chemistry involved in cocrystal formation, methods of preparation, their characterizations, and various applications in pharmaceutical and biomedical fields.

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization.

Crystallization is an important and difficult to control unit operation in the pharmaceutical industry. Crystallization can control molecular (i.e., polymorphism) and particulate (i.e., particle size and crystal habit) properties of active pharmaceutical ingredient (API). Moreover, these molecular and particulate properties govern the manufacturability, stability, and biopharmaceutical performance of the API and drug product. Nucleation is a key step and primary heterogeneous nucleation is a common mode of nucleation during crystallization. Hence, it is important to understand the parameters affecting primary heterogeneous nucleation, to achieve desirable properties in crystalline APIs. Primary heterogeneous crystallization has usually been linked to the surface characteristics like topography and functionality of the heteronucleant. The review outlines recent findings in the primary heterogeneous crystallization with specific emphasis on its pharmaceutical applications including regulatory considerations. Molecular-level mechanisms governing heteronucleation and subsequent outcome in terms of molecular as well as particulate-level properties of API have also been discussed. Moreover, general guidance for the selection of heteronucleant has also been included. Heterogeneous crystallization is a promising tool for efficient crystallization of API having properties for optimal pharmaceutical performance.