Many of the drugs that are marketed take the form of solids. The advantages of having drugs in solid dosage form are because it is usually a more stable and less invasive form compared to other forms such as suspensions which may result in caking if not formulated properly, suppositories that are subjected to the temperature of the environment and intravenous solutions. In developing a new pharmaceutically acceptable drug especially drugs in solid forms for example tablets and capsules, polymorphism and solid-state must be taken into consideration as those are the two crucial factors concerned. Different polymorphs give rise to diverse properties of the same drug. Physical properties such as density, melting points, solubility vary with different forms of polymorphs.
Polymorphism is defined as the capability of the drug compound to occur in two or more crystalline phases forming different types of arrangement for the same chemical compound or crystal lattice1. Each form of the drug has properties that are of pharmaceutical importance. One form of drug may transform into another under specific conditions2. Solubility of any solid-state depends on crystal structure. Following that, the process of dissolution depends on the solubility of a drug. Consequently, bioavailability of a pharmaceutical dosage is dependent on the rate of dissolution3. Therefore, the key parameter is the crystal structure of a pharmaceutical compound.
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Moreover, other factors that affect the stability of solid dosage forms are pH of the environment that the drugs are subjected to, for example the pH in the stomach and the pH of the small intestines are different with the latter one being more basic. Enteric coated tablet is made to control the release of APIs in a more specific manner. The tablet itself has a coat that will degrade depending on the pH that it is subjected to in the body. That is the reason why the rate of dissolution and thus, the rate of release of the API are influenced by the pH.
Crystals consist of two solid forms, the amorphous form or the non-crystalline form and the crystalline solid-state. The crystalline form is held in place by mainly hydrogen bonds and exhibits polymorphism4. The fundamental building block for each crystal structure is the unit cell. Crystal structure has a 3-Dimensional conformation and consists of atoms, ions and molecules that are packed closely together, where the free energy of the structure is at its minimum5. The unit cell has shape and size determined by distances in Armstrong units and angles measured in degrees5. The same chemical compound has various polymorphs differing in crystal structure and unit cells, and thus in solubility.
On the other hand, amorphous form of crystals is not long range highly ordered molecule and usually has a higher solubility compared to their crystalline form counterpart5. This non-distinct shape form has reduced chemical stability. It is distinguishable from the crystalline form because it does not have unit cells, having no specific arrangement and it does not exhibit Bragg diffraction of X-rays6. It differs from the crystalline solid form in terms of rate of dissolution, stability, solubility, hygroscopicity and other physicochemical properties.
The other solid state form is solvates. They are crystal structure that incorporates solvent molecule within the lattice either in stoichiometric or non-stoichiometric ratio1. If the solvent within the structure is water, the term hydrate is used1. Solvates differ from co-crystals in terms of the states of the components they contain. Solvates has at least one component which is liquid at room temperature4. Although solvates often improve dissolution rate, its disadvantage is that it is unstable, resulting in solvent loss during storage over a period of time3.
Salts are ionized molecules of the crystals. Active pharmaceutical ingredient (API) in the form of salt has an acidic centre or a basic centre. The common pharmaceutical cations for acidic centre are sodium, calcium and potassium whereas the acceptable pharmaceutical anions for basic drugs are hydrochlorides, sulphates and glucoronates5. Salts are important in pharmaceutical formulation or sciences as salts are ionized molecules resulting in rapid dissolution when administered into the body. Salts present in the pharmaceutical product are either in crystalline form such as tablets or in solvents for injections. Nevertheless, not all API are able to form salts on the grounds that they are neutral compounds and cannot be ionized. Therefore, co-crystal is a more preferred alternative solid-state form.
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Co-crystals, also known as multi-component crystals comprise of at least two different fundamental compounds7. A pharmaceutical co-crystal incorporates an API and one or more solid known as co-crystal former at room temperature. The API is the host and a secondary molecule noted as a guest molecule which is usually an acid and both molecules make up supramolecular heterosynthons by forming mainly hydrogen bonds8 without the transfer of the hydrogen atom from one molecule to another in the case of salts9. Other interactions include p-stacking and Van der Waals forces4. Co-crystals are usually more superior in comparison with their crystalline solids in terms of physical properties on the grounds that co-crystals have improved dissolution rate aiding bioavailability and have better chemical stability10.
Crystallisation is one of the steps in controlling solid-state form in pharmaceutical development. The primary factors that affect the shape and size of the crystals form are the choices of solvent used in crystallization and the crystal structure of the compound used11. Crystallization is denoted by the collision of molecules resulting in the formation of nucleus. There are various techniques of crystallization. One of the most common techniques used is the solution crystallization12. During the process, supersaturated solution containing the compound studied is obtained13. Thereafter, nucleation occurs and following that there will be crystal growth in the solution13. Nucleation is term as a molecular assembly process13. A phase change from solution to crystals will occur when the exact number of molecules are acquired13.
It is important to control the solid-state forms for the safety, efficacy and purity of the API. Processing may change the rate of dissolution and chemical stability due to phase transformation. Phase transformation arises from a few factors. Firstly, APIs that are subjected to stress, for example milling process have a tendency to transform from one solid-state to another and consequently the amount of free energy in the structure may increase, forming disordered phase14. Moreover, through processing thereâ€™s a possibility of introducing a condition where another solid-state form with minimal free energy arise14. These undesirable phase transformation are minimized through screening and analytical techniques.
In the attempt to produce solid dosage form, the possibility of acquiring an undesirable solid-state form may occur. That is the reason why screening techniques are required to ensure that the appropriate solid forms are founded.
There are many ways to screen for co-crystal formation. In order to improve the screening efficacy for potential co-crystal candidates, the most efficient and selective screening technique must be determined. In the formation of co-crystals, the conventional solution based techniques are often used15. These are solvent evaporation, cooling and addition of anti-solvent15. However, these techniques depend on a few factors, the selection of the solvent system, temperature and the concentration added15. Other methods include sublimation and growth from the melt slurries.
The anti-solvent addition co-crystallisation is an alternative to the cooling and evaporation technique. It is based on the concept of supersaturation in crystallisation16. Co-crystals are formed under supersaturated condition according to the solid-liquid separation theory17. The extent of supersaturation is affected by the addition of an anti-solvent. It should be noted that the choice of anti-solvent must be one that is soluble in the solvent but should be inert towards the API and co-former16. The function of anti-solvent is to reduce the solubility of the co-crystals formed in the solvent, resulting in supersaturation, and thus, the precipitation of co-crystals17.
Melt slurries or slurry screening technique is a method of producing co-crystals through equilibration of the APIâ€™s slurry or suspension (mixture of solid-state sample and a suitable solvent) and the slurry of the co-former18. Both the solids used are in stoichiometric ratio18. Through the solution the co-former come into contact with the API when both slurries are mixed. The fundamental of this technique is based on thermodynamics19 and that co-crystal solid will form when the activity of the co-crystal former is high and stops when the equilibrium shifts to the right or left18. After a period of equilibration, the solids obtained are analysed using powder X-ray diffraction (PXRD) through comparison of existing PXRD patterns18. The advantages of using this screening technique is that only co-crystallisation will occur and not the crystallisation of drug and coformer individually provided that there is no nucleation of the drug nor the coformer18. Furthermore, as long as there is a co-crystal phase, co-crystallisation is maximized using this screening method18. Lastly the experimental procedures for this technique are relatively easy to bring about and require less skill18.
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Non-solution based techniques does not need to take into account the polarity of the groups in the API because these techniques of co-crystallisation does not involve solvent. Therefore, the solubility of the API and the co-crystal former in the solvent is not concerned. Examples of the non-solution based techniques are thermal microscopy and grinding of two solids or ball milling to form co-crystals.
Grinding method is a useful screening technique found in the late 19th century4. It can be conducted with or without solvent. Solvent-drop grinding method uses a minute amount of solvent that the compound is soluble in to speed up co-crystallisation20. It is a method useful for producing different solid forms during pharmaceutical drug development as it is practical way for polymorph control and distinguishes between wide-range of polymorphs, selecting only the relevant ones. This fairly new technique of solvent inclusion is usually used when co-crystals are form from solution and not from basic ball milling technique4. Solvent may play a part in the nucleation process of co-crystals and it seems to be an essential component in developing a particular co-crystal from solution, speeding up the kinetics and facilitating co-crystal formation4, 20. Inability to produce co-crystal through grinding may be due to failure in forming co-crystal arrangements and it is not related to the stability of the compounds used4.
Hot-stage microscopy screening method or also known as the Kofler technique incorporates melting of two solids, adjacent to each other on a microscope slide to screen for co-crystals4. At a suitable temperature and condition, complex or co-crystal may be able to form beneath the cover slip at the interface between the two compounds consisting of the API and the co-crystal former respectively4.
The co-crystal structures that are newly developed by co-crystallisation are ascertained by a diverse range of analytical methods that are able to study the solid-state in the pharmaceutical products. The analytical techniques incorporates melting point determination, studies of the solubility of drugs in different solvents, spectroscopic methods such as Raman spectroscopy and IR spectroscopy, thermal analysis including Differential Scanning Calorimetry (DSC) and X-ray diffraction ( single crystal and powder).
In this experiment, the primary analytical steps are essentially the Raman spectroscopy and IR spectroscopy. Raman spectroscopy detects changes in the structure of APIs, for example different polymorphic forms, through the vibrational energies of the chemical bonds21. The advantages of using Raman spectroscopy are that it is a non-invasive technique, the compound is retained after the analysis and it analyses the structures of the APIs in a matter of seconds21. For an API which exhibits high intensity fluorescence, Raman poses a drawback as it is less accurate in obtaining fluorescent compoundâ€™s spectrum21. This issue can be solved by adjusting the laser wavelength of the instrument21. Infrared (IR) spectroscopy is a technique similar to Raman spectroscopy and both are fundamentals in identifying the characteristics of co-crystals through bond vibrational energies22.
IR spectroscopy can be used to quantify the extent of crystalline state and amorphous form in the compound because the magnitudes of the vibrational bands are proportional to the concentration of the different phases22. The intensities of the peaks from the IR depict the characteristics of different crystalline state22. IR spectroscopy is usually used to revalidate data obtained from the Raman spectrophotometer.
DSC is a type of thermal analytical technique founded on the basis of thermal energy22. The sample concerned is heated linearly until the melting point is reached and phase transitions are detected and scanned by comparing with the reference compound22. The difference in the amount of heat lost, exothermic process or the amount of heat absorbed, endothermic process in comparison to the reference can be evaluated by the DSC instrument22.
Analytical technique using the concept of diffraction is one of the most absolute methods in determining molecular order of any system that is important pharmaceutically.
The single-crystal X-ray diffractometry (SXRD) is a conventional way used to determine the 3-Dimensional structure of crystals or co-crystals6. The X-rays are diffracted according to the patterns formed by the different solid forms6. It is an accurate way of analyzing the compound obtained6. However, co-crystals of suitable size and quality are the main criteria to use this instrument and it can take a very long time to produce crystals of high quality that are suited for this analytical method4.
Powder X-ray diffraction (PXRD) is a simple quantitative method which measures the difference of the order of atoms or molecules in a powdered form sample22. It is an appropriate method to study different solid state forms such as polymorphism, salts and co-crystals23. Crystalline or co-crystal solid patterns are characterized by strong diffraction peak while the amorphous form has diffused and halo diffraction patterns22. The degree of crystallinity is determined by measuring the extent of X-ray scattering22. Nonetheless, PXRD has its disadvantages which are the inability to differentiate isostructural crystals, extended time needed to measure the compound and to certain extent, the reduction of preferred orientation effect22.
In recent years, crystal engineering has focused more on the field of developing co-crystals which has the capability of improving bioavailability of active pharmaceutical ingredients (APIs) that are poorly soluble in the body. These include some of the Biopharmaceutics Classification Systems (BCS) Class II compounds that have high permeability but low solubility.
Norfloxacin (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid) is a type of broad spectrum antibiotic under the class of Quinolones or more specifically it is a fluroquinolone antibiotic24. It is usually indicated for upper and lower urinary tract infections. The solubility profile of this drug is towards the lower end of the spectrum. Norfloxacin consist of a carboxylic group and a piperazine group. It exists in the zwitterionic form in aqueous solution24. The basic amine of the piperazine group and the acidic carboxylic group in the structure contributes to the acid/base interaction in forming zwitterions. However, its zwitterions characteristics cause Norfloxacin to be poorly soluble in water, at approximately pH 7 with a solubility range of 0.28-0.40 mg/ml24. Poor rate of dissolution results in difficulty in the formulation of Norfloxacin into both the solid dosage form such as tablets and also the liquid formulations.
Norfloxacin is chosen as the API for this study because of its low aqueous solubility. Thus, poor rate of dissolution is a good reason to conduct this research25. Furthermore, from the carboxylic group of Norfloxacin has a possibility of forming hydrogen bonds or pi-stacking bonds with co-crystal formers which is the characteristics of co-crystals. Following recent studies, a number of Norfloxacin co-crystals have been formed to improve the aqueous solubility of Norfloxacin24. For example, Norfloxacin anhydrate forms co-crystal of Norfloxacin with Isonicotinamide and Norfloxacin anhydrate salt cocrystal with succinic acid, malonic acid and maleic acid24. Based on researches, Norfloxacin exists in hydrates and two types of polymorphic form, enantiotropic form A and form B respectively24. Further studies are still ongoing to discover new co-crystals of Norfloxacin to modify the properties especially the dissolution rate of to have the desired physical and chemical properties of the drug.
The aim of this study is to design new co-crystal(s) to improve the solubility profile of the API, Norfloxacin for better bioavailability of the drug when delivered into the system of the body. To widen the chance of obtaining co-crystals, different co-formers, succinic acid, malonic acid, glutaric acid and oxalic acid are employed to form co-crystals with Norfloxacin through hydrogen bonding. Raw data of both the API crystalline solid and the crystal co-formers should be collected so that comparisons can be made when thereâ€™s a possibility of acquiring co-crystals.
Identification of the most suitable solvent for both the API and the co-former is essential. Apart from that, the screening methods described are useful to look for promising new co-crystals candidates, eliminating other solid-state forms. The validation of new co-crystals can be made by subjecting the compounds to several analytical techniques. The study of the wide-range of solid-state of Norfloxacin can be performed to further understand the different forms of Norfloxacin. Overall, the outcome of developing new co-crystals will benefit the pharmaceutical field and definitely the population.