An Overview of the Design, Formulation, and Characterization of Drug–Drug Co-crystals

Many medications with poor aqueous solubility have been found in recent years. About 60–70% of the molecules in these newly identified medications belong to BCS Classes II (low solubility/high permeability) and IV (poor solubility/low permeability). Because of their poor water solubility, which results in limited medication bio availability, many active pharmaceutical ingredients (API s) have not been created in formulations. Because different sections of the gastrointestinal system have varied pH values, medications administered orally have varying solubilities in gastrointestinal fluids at different pH values. This frequently results in nonlinear and variable absorption, making it difficult to assess the safety and effectiveness of medications. Because of this, a significant obstacle in the development of oral dose is the poor solubility of medications.

Etter was the first to report the term "co-crystal" and the design guidelines for hydrogen bonding in an organic co-crystal. The supra molecular synthon notion of hydrogen bond creation in crystal formations was initially introduced by Desi Raju. Depending on the kind of co-former, Duggirala and colleagues divided the co-crystals into molecular and ionic categories (1,4).
Co crystals are separated into eight categories:
1. An-hydrate co-crystals
2. Solvates, or crystal hydrates
3. An-hydrates of salt co-crystals
4. Salt co crystal hydrates (solvates).

Figure no: 2 Bio Pharmaceutical Classification

Amorphicity is described in terms of crystallization. Like crystallinity, amorphous solids may have short-range molecular order (i.e., in terms of the interactions between nearby molecules), but they lack well-defined molecular conformation and long-range molecular packing order. Amorphicity is advantageous for pharmaceutical materials because amorphous solids are more soluble, dissolve more quickly, and occasionally compress more effectively than their comparable crystals ⁽³⁾.

• Co-Crystals Preparation ⁽⁵⁾:
  Typical methods for preparing co-crystals:
  -Excessive addition of a co-crystal component might cause co-crystal separation by            decreasing its solubility.
  -The low percentage solvent area of the iso thermal ternary phase diagrams can be accessed using slurry crystallization.
  -Solvent identity is adjusted to optimize the co-crystal area in phase diagrams.
  -The components are wet milled, sometimes referred to as solvent drop grinding.
  -utilizing the amorphous or hydrated intermediate phase as a component of solid-state synthesis.  

Use Of Meta-Stable Poly Morphs: Using hot stage microscopy, co-crystal seeds from melt crystallization are used to seed solutions.

Figure No: 4 Potential Utility of Co Crystals

Drug Characteristics That Co-Crystallization Can Change ^(4,13):

The following are some instances of an API's in vivo (bio pharmaceutical) and in vitro (physicochemical) characteristics that can be established by co-crystallization:

Figure No 5: Alteration Properties of Co- Crystals

A theoretical process for deciphering supersaturated drug delivery systems the "spring and parachute" is a concept that is depicted in Pharmaceutics 2018, 10, 18, 12, 30. Similar to the drug's amorphous form, this abrupt occurrence may result in supra molecular aggregates or clusters of randomly orientated molecules lacking a high-level organization and periodic arrangement (spring effect) ⁽⁶⁾. The parachute effect, or maintenance of high solubility, can persist for a long period of time (120–300 min), because the transitions of these amorphous sums to stable crystalline phases and crystal development is expected to be a slow process that is prevented by polymers and excipients that are present in the stomach along with the drug. This high-energy amorphous phase is expected to fall into a meta-stable polymorphic form of the drug (of higher solubility), and eventually into a stable thermodynamic crystal form following Ostwald’s step rule, but until then, much of the drug will have been absorbed. The solubility of the co crystals has been reported in a variety of media (water, 0.1 N HCL, phosphate buffer, etc. Bio relevant dissolve media, such as simulated gastric fluids (SGF) or intestinal fluids (SIF), are    also utilized in solubility tests. Particle size may have an impact on dissolution.

Figure No: 6 The Spring and Parachute Concept ⁽⁷⁾

Advantages Of Cocrystals

In contrast to amorphous solids, it has a persistent crystalline shape. It can improve the solubility of medications that are not very soluble in water. Because of its improved solubility, it can also improve bio availability. Purification procedures may employ the co-crystal formation approach.

Preparation Of Co-Crystals ^(9,12):

5. Solvent Evaporation Technique^:

• The most popular method for creating co-crystals is this one. After being dissolved in a common solvent with an appropriate stoichiometric ratio, the components (API and co-former) totally evaporate.
  A thermodynamically favorable product is produced as a result of changes in the molecules' solution during evaporation, including the formation of hydrogen bonds between various functional groups.
  The choice of solvent has a significant impact on solubility. The component with the lesser solubility will precipitate if the two components have different solubilities. Solvent evaporation is a small-scale method that produces co crystals of excellent quality and purity without the need for complicated equipment.

5. Solid-state Grinding Technique or Neat Grinding:

This is a solvent-free co-crystallization technique. A mortar and pestle, a ball mill, or a vibrator mill are used to press and crush the solid components that will form the co-crystals once they have been mixed in the proper stoichiometric quantities. The typical grinding time is between thirty and sixty minutes. Many co-crystals can be made with this technique, and any failure is typically the result of using the wrong parameters. The specific surface area of interaction between the materials for the formation of inter molecular bonds increases when the particle size is reduced. When contrasted to co-crystallization via dissolving, this has the benefit of greater selectivity. It is easy to use and enables the desired co-crystal to be prepared quickly. Co crystals have been mixed with other substances that can also create co crystals with the API in experiments. In the latter scenario, the co-former is swapped out, which can be utilized to reveal different co-crystal modifications or evaluate how stable a co-crystal is when additional excipients are present. At first, just grinding was used to produce modifications that don't always occur during the dissolving process, such as the co-crystallization of caffeine and trifluoroacetic acid. In other words, it has also been applied to explain the hydrogen bond preference. Prognosticate-caffeine co-crystal was patented using mechanochemistry, or solid-state grinding.

5. Liquid-assisted grinding, or solvent-drop grinding:

By introducing a tiny quantity of solvent during the grinding process, this variation on neat grinding has been utilized to improve supra molecular selectivity in crystalline systems, both stoichiometric and polymorphic.
A very small amount of solvent (about a few tenths of an equivalent of solvent per mole of the component) is added after the two components have been mixed.
Since the solvent's little amount does not end up in the finished product, its effect can be characterized as catalytic. While many conformers are appropriate for co-crystallization, its benefits include greater crystallinity, enhanced performance, and the capacity to regulate the creation of poly-morphs. Since some co-crystals performed poorly in co-crystal formation after neat grinding for a long period, this approach increases the rate of co-crystallization. High-purity co-crystals can be produced with this technique with a markedly shorter preparation period.
Additionally, it makes it possible to synthesize specific polymorphic forms of co-crystals. For example, in co-crystals of caffeine and glutaric acid (1:1), neat grinding mostly (but not always) produced form I, whereas liquid-assisted grinding produced pure form I using a less polar solvent (such as cyclohexane or hexane). converted to pure form II using a more polar solvent (acetonitrile or water, for example).

Figure No:7 Schematic Presentation of Methods Applied in Co-Crystal Formation

Steps Involved in Formation of Co-Crystals:

1. Selection of API
2. Selection of co-former
3. Empirical and theoretical guidance
4. Co-crystal Screening
5. Co-crystal Characterization
6. Co-crystal Per-formation

RESULTS

State Characterization

Microscopic Studies:

Microscopic analyses were performed on both formulation and pure drugs (Ciprofloxacin, Ibuprofen). to forecast the results of compatibility and interaction investigations between two medications.  The co crystals containing ibuprofen and ciprofloxacin were made using evaporation and solvent-drop grinding methods. Only by grinding ciprofloxacin and ibuprofen in a (1:2) stoichiometry and adding ethanol was the pure form achieved. Ibuprofen and ciprofloxacin at a ratio of 1:1 were only made by solution crystallization from isopropyl alcohol. Using infrared findings, the co-crystals of ciprofloxacin and ibuprofen as well as their ethanol solvate were identified in this study. After 24 hours, the development of co crystals was able to enhance the stability and solubility of ciprofloxacin.

Figure No: 11 Isopropyl Alcohols

Figure No:12 Isopropyl Alcohol

Figure no:13 Butanol

Figure no: 14 Butanol

Figure No:15 Ethyl Acetate

Figure No:16 Ethyl Acetate

Figure no 17 Acetone

Figure no: 18 Acetone

FT- IR Studies:

FT-IR Studies were conducted for pure drug (Ciprofloxacin, Ibuprofen) and also Formulation. To predict the interaction and compatibility studies in between drug and the co-former.

Figure No:19 FT-IR of Pure Drugs and Ethanolic Co Crystals of Two Drugs

Co crystals were Analysed by FTIR SPECTROSCOPY to confirm the co crystal formation by comparing the spectrum with their respective starting materials.

Principle behind FTIR studies:

Fourier Transform is referred to as FTIR. The recommended technique for infrared spectroscopy involves passing infrared (IR) radiation through a sample. A portion of the infrared light is transferred through the sample, while the remainder is absorbed. A molecular fingerprint of the material was produced by the resultant spectrum, which showed the molecular absorption and transmission. No two distinct molecules emit the same infrared spectrum, just like a fingerprint. In Ciprofloxacin, characteristic peak observed at 3281.37cm‾. In Ibuprofen characteristic peak observed at 3252cm‾.
In combination found at 3278cm‾ so it is might be due to NH- group stretching.

Scanning Electron Microscopy (SEM):

SEM Analysis provides information about the samples surface morphology and particle size.

Fundamental principle of scanning electron microscopy (SEM)

Significant amounts of kinetic energy are carried by accelerated electrons in a SEM, and when the incident electrons are decelerated in the solid sample, this energy is released as a range of signals generated by electron-sample interactions. These signals include photons, visible light, heat, back scattered electrons (BSE), diffracted back scattered electrons (DBSE), and secondary electrons (which create SEM images). Backscattered electrons are best used to illustrate compositional disparities in multiphase samples (i.e., for quick phase discrimination), while secondary electrons are best used to display morphology and topography on materials. Inelastic collisions between incident electrons and electrons in distinct atomic orbitals (shells) within the sample are what generate X-rays. A set wavelength of X-rays is produced when excited electrons revert to lower energy states; this is connected to the difference in energy levels of electrons in various shells for a given element. Consequently, each element in a mineral that is "excited" by the electron beam produces distinct X-rays. Since X-rays produced by electron interactions do not cause volume loss of the sample, SEM examination is regarded as "non-destructive," meaning that the same materials can be analyzed repeatedly.

 Sem Discussion:

SEM is used to examine ciprofloxacin, ibuprofen, and their combination.  Double-sided adhesive tape was used to secure the powders to a brass stub, and they were coated in a vacuum inside a layer of room-temperature platinum to make them electrically conductive.