Skieneh JM; Rohani S

Review Article

Austin Pharmacol Pharm. 2017; 2(1): 1007.

Screening New Solid Forms of Pharmaceuticals to Enhance Solubility and Dissolution Rate

Skieneh JM and Rohani S*

Department of Chemical and Biochemical Engineering, Western University, London, UK

*Corresponding author: Rohani S, Department of Chemical and Biochemical Engineering, Western University, London, UK

Received: August 31, 2017; Accepted: October 12, 2017; Published: October 20, 2017

Abstract

Approximately 75% of the drugs that are being approved for use in the pharmaceutical industry have low aqueous solubility. This leads to issues with drug uptake, higher doses and consequently a negative environmental impact. One approach to improving these Active Pharmaceutical Ingredients (APIs) is to use the crystal engineering technique of adding another molecule into the crystal lattice of the API. The formation of a novel solid-state is dependent on the strength of the intermolecular bonds formed and the type of synthesis used. Main synthesis routes include a variety of solution crystallization procedures as well as Liquid Assisted Grinding (LAG) and neat grinding. This review will emphasize the formation of new states by adding a distinct molecule into the lattice of the API through non-ionic bonding. For this reason, polymorphs and salts will be disregarded and the main forms analyzed are co-crystals, solvates, eutectics, and co-amorphous materials. Appropriate choice of excipient as well as screening methods is also given in detail.

Keywords: Review; Co-amorphous; Co-crystals; Salts/salt selection; Solid solutions; Solid-state; Solvates

Introduction

Every year the Food and Drug Administration (FDA) approves New Molecular Entities (NMEs) for pharmaceutical use. As of May 2017, there have already been 20 Active Pharmaceutical Ingredients (APIs) accepted, this year. A Biopharmaceutics Classification System (BCS), depicted in Figure 1, is used by the FDA to classify APIs and reduce unnecessary human testing [1]. The BSC classification is as follows: Class I (high permeability, high solubility); Class II (high permeability, low solubility); Class III (low permeability, high solubility); and Class IV (low permeability, low solubility) [2]. When combined with dissolution studies, a biowaiver for in vivo bioavailability and bioequivalence can be applied for Class I and III drugs, which leads to a less vigorous testing required for these drugs [3].

Figure 1: BCS used by the FDA where highly soluble is considered when the highest dose strength is soluble in less than 250mL water over a pH range of 1 to 7.5, and highly permeable is considered when the extent of absorption in humans is determined to be greater than 90% of an administered dose [1].

    
    
    Figure 1:  BCS used by the FDA where highly soluble is considered when the
highest dose strength is soluble in less than 250mL water over a pH range of
1 to 7.5, and highly permeable is considered when the extent of absorption
in humans is determined to be greater than 90% of an administered dose [1].

A simple solution to help pharmaceutical companies with more efficient drug testing (i.e. less clinical testing) would be to stop using drugs that do not belong to Class I and III; however, approximately 75% of NMEs belong to BCS Class II and IV [4]. This means that the majority of effective medicines that are FDA approved drug innovations have a poor solubility in aqueous solutions. Many drugs today are designed using high throughput screening approaches to ensure valuable and successful products. Since the approval process for NMEs takes years, pharmaceutical companies want to guarantee that they have the best contenders. The screening processes tend to result in APIs that are higher in molecular weight and have increased hydrogen-bonding [5]. Increased molecular size tends to result in greater van der Waals interaction between like molecules, while more hydrogen bonding within the API creates a stronger crystal lattice. Both characteristics lead to a compound that is less soluble.

Why are low solubility drugs undesirable? First, they often require high doses to reach required therapeutic plasma concentrations after oral administration, hence patients are ingesting significantly more than necessary. The increase in dose also leads to more costly medicines, which is unfavorable to consumers and pharmaceutical companies. Poorly soluble APIs are also more vulnerable to food effects (e.g. some drugs are suggested to be taken after a fasting period due to reduced absorption in the presence of food), and slow dissolution can lead to lower fraction absorbed in the small intestine [6]. High levels of API excretion due to low absorption are costly to the pharmaceutical industry and can be detrimental to our environment. For instance, Carbamezapine, a routine API that is nearly insoluble in water, was found in every sample taken from wastewater treatment plants’ effluent of three different rivers in England [7]. Therefore, not only are Class II and IV drugs more expensive to administer, they also have a lasting effect on the environment. Taking these factors into account, a strong need to increase the solubility of these drugs is prevalent.

Crystal engineering is defined as: the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in the design of new solid forms with desired physical and chemical properties [8]. Numerous methods are present that involve altering the solid-state of Class II and IV APIs to increase water solubility and bioavailability. This altering of states is known as crystal engineering, and some of these approaches include formation of: salts, co-crystals, solvates, eutectics and co-amorphous mixtures. The bioavailability of a drug is affected by its aqueous solubility, dissolution rate, permeability, etc. If one can increase the water solubility of Class II drugs, the bioavailability will be greatly improved [9].

In this review, the practices discussed will focus on non-ionic bonding between distinct molecules, so salts and polymorphs will be overlooked. The techniques mentioned involve adding another component called an excipient into the crystal structure; excipients will usually have more ideal physical and chemical characteristics than the API, so the combination will lead to a superior drug formulation. The beauty of these methods relies on the fact that excipients are already approved by the FDA for use in pharmaceuticals, and thus, the novel solid-state of the API will not need to undergo new clinical studies.

Co-amorphous Mixtures

An amorphous solid, also referred to as a glass, has no long range molecular order of packing nor do its constituents have a distinct molecular conformation [10]. Amorphous materials have properties similar to liquids at a molecular level but are more like solids at a macroscopic level [11]. Due to the lack of order and since this form is the most energetic, amorphous compounds have been shown to have increased solubility in comparison to their crystalline counterparts [12]. Consequently, this will also result in an increase in bioavailability, so the formation of an amorphous pharmaceutical compound is an appropriate means to tackle the issues with Class II and IV drugs.

Co-amorphous solids, depicted in Figure 2, occur when two components become amorphous due to interaction with one another. Intermolecular bonding between API and excipient impedes the arrangement of individual molecules into separate lattices and results in an amorphous material [13]. Co-amorphous mixtures are shown to be not only high in solubility, but also have a high stability [14]. By adding another component into the system, the problem of low stability in amorphous materials is alleviated in co-amorphous materials. Amino acids are great candidates as excipients in these systems [15].

Figure 2: Representation of (a) crystalline API (hexagon) and excipient (rectangle), (b) amorphous API, and (c) co-amorphous API and excipient.

    
    
    Figure 2:  Representation of (a) crystalline API (hexagon) and excipient
(rectangle), (b) amorphous API, and (c) co-amorphous API and excipient.

An amorphous phase composed of a single material can be created through two main routes of production: either a thermodynamic or kinetic disordering process. Thermodynamic disordering occurs when the loss of long range order symmetry causes disorder in the solid-state. It allows for close random packing and is termed thermodynamic disorder due to the breaking of symmetry [16]. Kinetic disordering is referred to when long range disorder is caused by short range order. This process is considered to be continuous and can reduce crystalline material to glassy material [17]. When creating an amorphous state, the thermodynamic pathway involves starting with a thermodynamically stable non-crystalline form, such as a melt or solution. The melt will then undergo quenching, while the drug will precipitate from solution. Conversely, the kinetic pathway will start with a solid-state which is then converted by introducing crystal defects via crushing, milling or continuous shear forces [18]. These pathways are also applicable to the preparation of co-amorphous systems.

While still quite a new practice in drug formulations, coamorphous mixtures have been shown to be readily obtained by a variety of procedures. The main procedures are milling and grinding (kinetic disordering) or quenching/cooling and solvent evaporation (thermodynamic disordering). Given in Table 1 are some instances of co-amorphous mixtures and the methods used to produce them. These are all desirable techniques because not only are they quick to produce, they also only require a small amount of sample; however, not every technique is applicable to every drug-excipient combination. Quenching is not available if degradation occurs at higher temperatures, solvent evaporation can prove difficult if there are solubility differences, and milling may not apply enough force to disrupt the lattice.

Table 1: Preparation of Co-amorphous Systems.




  
    Drug 
    Excipient 
      (or drug) 
    Technique 
    Experimental 
  
  
    Curcumin
    Artemisinin
    Solvent Evaporation
    A mixture of 1:1    molar ratio of Curcumin and Artemisinin was dissolved in ethanol. The    solution was then rotovaped (fast evaporation under vacuum) to give the co-amorphous    product [19].
  
  
    β-azelnidipine
    Maleic Acid
    Grinding (LAG or    neat)
    β-azelnidipine and    maleic acid at molar ratios of 1:1 and 1:2 were placed into a 50mL stainless    steel jar and milled at 30Hz in a laboratory-scale oscillatory disk mill.    This can be done neat or with the addition of ethanol [20].
  
  
    Indomethacin
    Cimetidine
    Quenching
    Indomethacin–cimetidine    physical mixtures were melted on an aluminium foil placed on a preheated    hotplate (180°C) for 1 min. The molten liquid was cooled quickly by placing    the aluminum foil over ice water [21].



Table 1: Preparation of Co-amorphous Systems.

To classify a material as amorphous, perhaps the most effective method is to use powder X-ray diffraction (PXRD). Crystalline material will show very distinct and sharp peaks, while amorphous material will appear as one very broad peak termed a halo since it has no defined crystal lattice or symmetry operators. To further examine the characterization of a co-amorphous system, the first example in Table 1 will be considered. Curcumin, a poorly water-soluble molecule, has been shown to help increase anti-malaria effects when taken in parallel with the API Artemisinin. Instead of prescribing these and taking them separately, a co-amorphous mixture was formed via fast solvent evaporation so that a patient could take them together. The PXRD patterns of the starting materials and the mixture are shown in Figure 3 [19]. It is clear that the mixture has lost the crystalline nature of the starting materials and is now forming weak intermolecular interactions.

Figure 3: The PXRD patterns of crystalline Curcumin form I (CUR Form-I), co-amorphous Curcumin-Artemisinin (CUR-ART Co-amorphous), and crystalline artemisinin form I (ART Form-I) [19].

    
    
    Figure 3:  The PXRD patterns of crystalline Curcumin form I (CUR Form-I),
co-amorphous Curcumin-Artemisinin (CUR-ART Co-amorphous), and
crystalline artemisinin form I (ART Form-I) [19].

Depending on the method used for producing the co-amorphous mixture, obtaining an amorphous pattern from PXRD is sufficient for characterization. If prepared via grinding, then the product is usually co-amorphous; however, quenching may lead to degradation and solvent evaporation could lead to a single amorphous state precipitating out first. To ensure that both starting materials are present in the amorphous product, one should preform solution HPLC or 1H NMR (nuclear magnetic resonance). In the NMR analysis, if the 1H shifts seen are solely representative of both starting materials, then the product can be said to be co-amorphous. Keeping with the Curcumin-Artemisinin mixture, it was exhibited that chemical shifts for both starting materials were present in their product.

Solid-state NMR (ssNMR) is another method that can be used for the characterization of these systems. ssNMR will usually show broader bands for amorphous material compared to crystalline material due to the increase of molecular orientations [22]. There will also be a shift in peaks due to the intermolecular bonding between the drug and excipient [23]. Furthermore, when compared to the ssNMR spectrum of a purely crystalline homogeneous mixture of the starting materials, the amorphous content of the co-amorphous system can be determined [24]. However, this technique often relies on peak integration, which can prove to be difficult when there is an overlap (i.e. broad peaks in amorphous materials often result in an overlapping signals). Also, formation of the homogeneous mixture could result in decreased crystallinity that would introduce error. Another method is to compare with both the fully crystalline and fully amorphous spectra of the starting materials. This method uses Principal Components Analysis (PCA) of ssNMR data that is normalized by dividing all PCA scores by the score of the 100% amorphous sample after subtracting the score of the crystalline sample. The profile for rate of co-amorphization can be obtained by plotting the normalized data against mill time [25].

For further characterization, Raman and FT-IR (Fourier Transform Infrared Spectroscopy) can be conducted. For both techniques, the spectra will appear as a combination of the starting materials with small shifts in frequencies [26]. The peaks that have shifted when compared to the starting materials, are representative of the bonds involved in the intermolecular bonding that stabilizes and causes formation of co-amorphous mixtures [27,28]. When coupled with ssNMR, these characterization techniques are useful in proposing a bonding mechanism between components of the system. Following the ongoing example, the proposed bonding mechanism of Curcumin and Artemisinin in Figure 4 was determined by analyzing the FT-IR spectrum, which showed a shift in carbonyl stretching of Artemisinin and the phenolic alcohol of Curcumin.

Figure 4: Proposed bonding mechanism in the co-amorphous system of Curcumin-Artemisinin [19].

    
    
    Figure 4:  Proposed bonding mechanism in the co-amorphous system of
Curcumin-Artemisinin [19].

Fundamental thermal analysis of these systems can be carried out with Differential Scanning Calorimetry (DSC). Amorphous materials will undergo a glass transition at a specified temperature (Tg), above which the material will tend to crystallize [29]. The DSC data of a co-amorphous system will differ vastly from that of the starting materials. Once again, considering the Curcumin-Artemisinin system, the differences can be appreciated in Figure 5. The melting of the starting materials is seen in the endothermic peaks, while the co-amorphous system has a broad exotherm. The Tg is highlighted and appears below the melting of both Curcumin and Artemisinin. When plotting a phase diagram of a binary system using DSC, a “v” shape may appear for co-amorphous mixtures with a single thermal event happening at a particular molar ratio [30]. Since co-amorphous systems are not well studied, using DSC alone is not useful as its results are not universal (e.g. the formation of a “v” in the binary phase diagram is an ideal situation).

Figure 5: DSC thermographs of Curcumin (CUR), amorphous Curcumin (CUR-amorphous), co-amorphous Curcumin-Artemisinin system (CUR-ART) and Artemisinin (ART). Circled are the glass transition temperatures.

    
    
    Figure 5:  DSC thermographs of Curcumin (CUR), amorphous Curcumin
(CUR-amorphous), co-amorphous Curcumin-Artemisinin system (CUR-ART)
and Artemisinin (ART). Circled are the glass transition temperatures.

Co-Crystals

Much like co-amorphous systems, a co-crystal is composed of neutral, solid components that interact with each other through intermolecular bonding. A simple depiction of a 1:1 molar ratio cocrystal comprised of two different compounds is given in Figure 6. In this representation, the hexagonal component can represent the API, while the rhombus is the excipient. Intriguingly, individual components can be salts or hydrates so long as each is considered overall neutral [31,32]. Co-crystals have been known for some time by different names (e.g. addition compounds, mixed binary molecular crystals, molecular complexes, solid-state complexes, heteromolecular crystals, etc.), but have not been of great interest until recently [33]. To avoid being ambiguous between solid-states, the FDA gave the following definition to co-crystals: solids that are crystalline materials composed of two or more molecules in the same crystal lattice [34]. In a pharmaceutical co-crystal, at least one of these components will be an API; the excipient is referred to as the cocrystal former or co-former [35].

Figure 6: Representation of a two-component co-crystal in a 1:1 molar ratio, where both hexagons and rhombuses represent a solid, neutral component.

    
    
    Figure 6:  Representation of a two-component co-crystal in a 1:1 molar ratio,
where both hexagons and rhombuses represent a solid, neutral component.

Co-crystallization occurs when an excipient is introduced that competes with and supersedes the intermolecular bonding of a molecule with itself [36]. The most difficult task in co-crystal formation is picking an appropriate co-former, which will be discussed later on. The main intermolecular force behind co-crystal formation is hydrogen bonding, so the co-former should have appropriate Hydrogen Bond Donors (HBD) and Acceptors (HBA). There are additional contributing factors to co-crystal formation, and a statistical review of co-crystals in the CSD (Crystal Structure Database) leads to some general assumptions: co-crystals form between molecules of similar shape and polarity, and the number of HBD/HBA is less important than the strength of the potential hydrogen bonding [37]. For instance, if an API has multiple functional groups and one is carboxylic, it will tend to have greater potential for forming a co-crystal with an excipient containing an amide than with an excipient that can form multiple weaker bonds. Furthermore, if an API shows potential for intermolecular bonding with an excipient due to matching the HBD and HBA groups, a co-crystal may not form if the shapes do no match (e.g. planar molecules will tend to form co-crystals with planar molecules).

The formation pathways for co-crystallization are comparable to those for co-amorphous mixtures and include Liquid Assisted Grinding (LAG) and dry/neat grinding, solvent evaporation, isothermal slurry conversion, cooling crystallization, anti-solvent crystallization, spray drying and rapid expansion of supercritical fluids. Provided in Table 2 is a summary which highlights examples of each method.

Table 2: Some Preparation Techniques for Co-Crystal Synthesis.

Drug
Co-former
Technique
Experimental

Theophylline
Citric Acid
Neat Grinding
0.150g of an equimolar combination of theophyllinecitric acid and citric acid was placed into a 25mL stainless steel grinding jar and ground for 1h using two stainless steel balls 7mm in diameter. The overall temperature of the reaction mixture remained below 35°C [38].

Adefovir Dipivoxil
Glutaric Acid
LAG
1:1 mole ratio of Adefovir Dipivoxil and Glutaric Acid was ground using an agate mortar and pestle for 20-30 min. Methanol was added dropwise over the course of grinding (0.5mL/mmol cocrystal) [39].

Fenofibrate
Nicotinamide
Solvent Evaporation
A mixture of FNO and nicotinamide in 1:1 molar ratio was dissolved in 20mL of ethanol with sonication (to induce saturation) and was kept overnight to evaporate solvent. The crystals obtained after evaporation of ethanol were dried in air [40].

Trospium Chloride
Salicylic Acid
Quenching
A 1:1 physical mixture of Trospium Chloride with salicylic acid was prepared and heated at 10°C per min under nitrogen purge above eutectic temperature. The mixture was then cooled to room temperature at a cooling rate of 10°C per min. After the mixture stood at 30°C for 60 min, the heating was repeated and the co-crystal was obtained [41].

Indomethacin
Saccharin
Anti-solvent Addition
In a 1L double jacketed reactor, predetermined amounts of Indomethacin and saccharin were fully dissolved in methanol (300mL), and 150mL of purified water as anti-solvent was added to the solution using a peristaltic pump. The process was performed for 30 min and the product was filtered and dried under vacuum.

Theophylline
Glutaric Acid
Slurry Conversion
Equimolar mixture of theophylline and glutaric acid was added into chloroform to form slurry at 50°C. This slurry was seeded with crystals from co-grinding of theophylline and glutaric acid and co-crystals formed as solvent evaporated.

Theophylline
Saccharin
Spray Drying
A 0.9% equimolar solution of Theophylline and saccharin in ethanol were spray dried at an inlet temperature of 120°C and outlet temperature of 77°C to give a co-crystal. The feed rate was 5mL/min, the air flow was 536L/h and the aspiration was 100% [42].



Table 2: Some Preparation Techniques for Co-Crystal Synthesis.

The most advantageous way to characterize a co-crystal is by growing single crystals and running X-ray diffraction. This technique will give the stoichiometric ratio, crystal lattice and intermolecular bonding of the molecular structure [44-47]. Single crystal X-ray diffraction alone is adequate for identifying co-crystal formation. However, while it is the most useful, obtaining single crystals is often challenging and not always possible. Since many co-crystals are formed using mechanochemical techniques, access to single crystals is often not possible [48]. Also, changing to conditions necessary to form high quality crystals can sometimes cause components to crystallize independently. In these scenarios, other techniques can be employed to characterize the suspected co-crystal.

ssNMR is a practical characterization technique in helping elucidate the structure of co-crystals. It has even been shown that ssNMR can be used to monitor co-crystal formation in situ [49]. This method can be used for small amounts of sample, is noninvasive and can adequately analyze multiphase systems [50]. Using 1D and 2D ssNMR techniques can lead to the determination of the intermolecular bonding sites within co-crystals [51]. When coupled with PXRD and Density Functional Theory (DTF) calculations, 1D ssNMR can be employed to determine the molecular structure of a co-crystal. For example, a theophylline-nicotinamide co-crystal has been formed by LAG or slow evaporation with ethanol and is shown to have improved solubility and hygroscopicity compared with the anhydrous API [52]. Characterization techniques and crystal engineering knowledge can be used to interpret intermolecular bonding sites in the co-crystal. Next, this suggested bonding between the API and excipient was refined using DTF method, and the ¹³C and 15N ssNMR spectra were predicted. These were then compared to the spectra that were obtained experimentally and validated the refined structure of the theophylline-nicotinamide co-crystal [53].

PXRD is also particularly useful; if a co-crystal is formed then the crystal lattice will change, resulting in a powder pattern that is distinct from the starting materials. This concept can be easily visualized by examining the theoretical PXRD patterns of an API, coformer and their corresponding co-crystal in Figure 7. It has also been demonstrated that PXRD can be utilized to help determine the purity of the co-crystal formed. This is done by formation of a calibration curve using known amounts of co-crystal and then monitoring the most intense peak in the PXRD pattern that has the least amount of overlapping [54].

Figure 7: Theoretical PXRD patterns of (a) API (b) co-former and (c) their co-crystal.

    
    
    Figure 7:  Theoretical PXRD patterns of (a) API (b) co-former and (c) their
co-crystal.

Thermal analysis is also critical in the analysis of co-crystals [55]. Akin to the PXRD patterns, DSC thermographs will result in data that is different from the starting materials. The thermographs of co-crystals usually show an endothermic peak for co-crystal melting that is above or below the melting of the API and co-former [56]. Ideally, the co-crystal will have a lower melting point than the API; this will result in intramolecular bonds that are easier to break and increase the drug’s aqueous solubility [57]. DSC can also be employed to prepare a phase diagram for the system. When plotting the onset of peak one and the peak temperature of peak two at varying molar ratios, the result is a sort of “w” shape [58]. The region between the two eutectic peaks is the co-crystal forming region. This phenomenon is more suitably explained with the aid of an image (Figure 8) [59].

Figure 8: Theoretical phase diagram of a binary system capable of co-crystal formation.

    
    
    Figure 8:  Theoretical phase diagram of a binary system capable of co-crystal
formation.

Figure 9: (a) molecular structures of API (hexagon) and excipient (triangle), (b) and (c) are both examples of discontinuous interaction between API and excipient found in eutectic mixtures. These arrangements can interact with each other throughout the mixture [67].

    
    
    Figure 9:  (a) molecular structures of API (hexagon) and excipient (triangle),
(b) and (c) are both examples of discontinuous interaction between API and
excipient found in eutectic mixtures. These arrangements can interact with
each other throughout the mixture [67].

Obtaining PXRD and DSC data that validates the presence of a co-crystal is sufficient in claiming co-crystal formation. To acquire the stoichiometric ratio, integration techniques of solution 1H NMR can be employed. For example, if a single proton in the API is normalized to one and a chemical shift representing three protons in the excipient integrates to three, then the co-crystal ratio is 1:2 API: co-former. If single crystal XRD and/or ssNMR have been attained, then Raman and FT-IR are not necessary. However, if not attained, these techniques will show a change in stretching frequencies which will imply that certain bonds are involved in intermolecular bonding and help to determine what supramolecular synthons are being formed [60,61]. DSC can be coupled with FT-IR as a very quick and easy means of co-crystal confirmation. By comparing the changes in IR frequencies as a binary system is heated, one can confidently see where co-crystal formation occurs [62]. Often times a combination of all or multiple techniques that have been mentioned are used to ensure a complete characterization so that co-crystal formation is irrefutable.

Eutectics

Like co-crystals and co-amorphous mixtures, eutectics comprise of multiple components that are neutral at ambient conditions. A pharmaceutical eutectic mixture comprises of API(s) and excipient(s) that do not interact to form a novel compound, but will impede the crystallization of each other at certain molar ratios [63]. These interactions are short range [64]. Formation of eutectic mixtures is a useful method for weakening the intermolecular bonding of a crystalline material. This will reduce the melting point of a system, which will ultimately increase the solubility. The solubility is also increased due to the reduction in particle size (and consequently the increase in surface area) found in eutectics compared to the separate crystalline components [65], Figure 9 is a visualization to help comprehend the concept of eutectics: if the hexagon and rhombus characters shown in (a) are representative of the crystal structures of API and excipient, then (b) and (c) are ways in which they can interact. These different types of interactions will be found discontinuously within the eutectic mixture and can interact with each other [66]. The components of a eutectic mixture are miscible in the liquid state, but only slightly in the solid-state. At a eutectic composition, the API and excipient will crystallize out at the same time; while at any other molecular ratio one component will start to crystallize distinctly [67].

The synthesis of eutectic mixtures is comparable to that of other solid-states. Usually the same techniques are employed and will simply result in a eutectic instead of a co-crystal or co-amorphous mixtures due to the strength of the interactions between API and excipient. The most common techniques include melting, grinding and solvent evaporation; some examples are displayed in Table 3.

Table 3: Some Synthesis Techniques of Eutectic Mixtures.




  
    Drug 
    Excipient (or drug) 
    Technique 
    Experimental 
  
  
    Curcumin
    Nicotinamide
    Grinding
    Curcumin and    nicotinamide were taken in a stoichiometric ratio and subjected to    solid-state grinding in a mortar-pestle for 15 min [68].
  
  
    Acetaminophen
    Caffeine
    Melting
    A stoichiometric    mixture of Acetaminophen and caffeine was heated to a temperature 2°C above    complete fusion of both compounds. The mixture was stirred, cooled to room    temperature and gently ground (using a mortar and pestle) [69].
  
  
    Aspirin
    Paracetamol
    Solvent Evaporation
    A different    proportion of Aspirin and Paracetamol was dissolved in a methanol:dichloromethane    (3:1) solution; the solvent was evaporated rapidly under vacuum [70].



Table 3: Some Synthesis Techniques of Eutectic Mixtures.

Eutectic mixtures are an emblematic product when screening for pharmaceutical co-crystals; consequently, the same techniques are employed for characterization. The initial step is typically to run PXRD due to its capacity for rapid analysis. The PXRD pattern for a eutectic mixture differs from that of co-crystals and co-amorphous mixtures since they are characterized by a pattern that is a combination of the starting materials (similar to a physical mixture) as opposed to one that is unique [71]. This distinguishing characteristic is due to API and excipient retaining their molecular structures while still capable of intermolecular bonding.

Obtaining a PXRD pattern of this nature is not sufficient for eutectic confirmation as it may simply be a physical mixture of the components; the next step in characterization would be DSC. The thermograph for a eutectic mixture will usually appear as a melting endotherm that occurs at a temperature below both API and excipient melting [72]. A physical mixture differs and will show two distinct melting points, since the constituents are not interacting [73]. At a specific ratio, this endotherm will appear as a single peak resembling a co-crystal; however, since the PXRD pattern is not distinct, it is known to be a eutectic and no exothermic events will occur [58]. Running DSC at different molar ratios and plotting the binary phase diagram (as previously described) will result in a graph that has a “v” shape similar to Figure 10.

Figure 10: Theoretical phase diagram of a binary system which forms a eutectic.

    
    
    Figure 10:  Theoretical phase diagram of a binary system which forms a
eutectic.

These two techniques, PXRD and DSC, are typically sufficient in determining if a eutectic has formed. Solution 1H NMR can be run to confirm stoichiometric ratios. FT-IR, Raman and ssNMR will all mirror PXRD in terms of obtaining result that reflect a combination of the starting materials.70 Confocal Raman Microscopy has been employed to show discontinuous bonding in eutectic mixtures by monitoring characteristic bonding peaks [74].

Solvates

Contrary to the previous solid-states that have been discussed and consist exclusively of solid materials at room temperature, a solvate comprises of multiple components where solvent(s) has been incorporated into the crystal lattice [75]. A special case, termed a hydrate, occurs when solvent involved is water [76]. Liquid solvent at ambient conditions can be found in both stoichiometric and nonstoichiometric amounts, as depicted in Figure 11 [77]. A solvate is described simply as any crystal composed of a solvent molecule and either a co-former or a cation-anion pair (Figure 11(c)). When the components are found in stoichiometric amounts, this is referred to as a “true solvate” (Figure 11(b)) [78].

Figure 11: Representation of (a) crystalline API (hexagons) and solvent (small circles), (b) stoichiometric or ‘true” solvate, and (c) non-stoichiometric solvate.

    
    
    Figure 11:  Representation of (a) crystalline API (hexagons) and solvent
(small circles), (b) stoichiometric or ‘true” solvate, and (c) non-stoichiometric
solvate.

Pharmaceutical solvates will contain an API as a co-former or pharmaceutical salt as the cation-anion pair. Solvent can incorporate into the voids of the crystal lattice and is recognized as channel solvent [79]. These types of solvates will retain their crystal structure if the solvent is removed and can be found in stoichiometric or non-stoichiometric amounts [80]. Another type involves stronger intermolecular bonding between the solvent and the solid that results in a distinct and more stable crystal lattice. In this scenario, functionality is a more vital factor in solvent inclusion [81]. The extent of stabilizing, intermolecular bonding found in these solvates includes: hydrogen bonding, halogen binding, metallic bonding and van Der Waals Interactions [82,83].

Since solvent (especially water) is present in many stages of pharmaceutical production, solvates are an interesting means of increasing the solubility and stability of drugs. Water and many other solvents have potential to form strong hydrogen bonding interactions with a variety of molecules that could result in the formation of a crystal lattice with increased stability. Removing solvent can lead to the decomposition of the API or ruin its crystal lattice [84]. Instead of trying to remove solvent from the system as waste, alternatively, it can be incorporated (so long as it is safe for ingestion).

Synthesis of solvates is usually achieved via cooling and/or evaporative crystallization from solution. Both methods rely on supersaturation to promote crystal growth. Solvates have also been formed via grinding [85]. A case for the synthesis of each type of solvate is given in Table 4.

Table 4: Cases Representing the Synthesis of Different Types of Solvate Systems.




  
    Solvent 
    Solvate Type 
    Experimental 
  
  
    Isopropanol
    Stoichiometric    Channel
    Atorvastatin was    stirred in a minimum amount of acetone and isopropanol just below boiling    point for over 24h. The solution was filtered, water added as anti-solvent    and the product is allowed to crystallize in air at room temperature [86].
  
  
    Water
    Non-stoichiometric    Channel
    Solvate was    crystallized from a 2-propanol: water (8:2, v/v) mixture in air at room    temperature [87].
  
  
    Cyclohexane 
    Stoichiometric Lattice Inclusion 
    Solvate isolated by vapor diffusion of cyclohexane into a toluene    solution of Dirithromycin [88].



Table 4: Cases Representing the Synthesis of Different Types of Solvate Systems.

After a solvate has been formed, one needs to properly characterize it. Once again, single crystal XRD is the all-telling technique for characterization. The data obtained will result in the molecular structure which can be used to establish the intermolecular bonding between components, whether a “true solvate” has been formed, if the solvent is located predominantly in the voids. To explore this method, an Esomeprazole Magnesium solvate, displayed in Figure 12 will be investigated. Esomeprazole Magnesium is a poorly soluble pharmaceutical salt with low stability. In this solvate, water is bonded in two distinct modes: strong dative-covalent bonding directly with Mg and in the voids of the crystal lattice. The former water molecules are bonded more powerfully than the latter. The 1-butanol molecules are also found in the channels and can be seen to form hydrogen bonds with water. This compound is determined to be a “true solvate” with respect to the water molecules, and butanol is found in nonstoichiometric amounts.

Figure 12: Esomeprazole Magnesium solvate with water and 1-butanol. Hydrogen bonding between molecules is shown in blue [78].

    
    
    Figure 12:  Esomeprazole Magnesium solvate with water and 1-butanol.
Hydrogen bonding between molecules is shown in blue [78].

Since single crystals are often not easily attainable, there are a variety of other techniques that can be used for characterization. PXRD is particularly useful when the solvate is synthesized via the formation of a new crystal lattice that incorporates the solvent. This will result in a PXRD pattern that is novel in comparison to the API [86]. Conversely, if the solvent is simply filling the voids in the crystal lattice, the PXRD pattern will appear to be analogous to that of the API with very slight differences. In this situation, it is necessary to conduct further analysis, such as ssNMR, to ensure that a solvate has indeed been formed [87]. An outstanding illustration of this is seen in Figure 13; ¹³CssNMR spectra are taken for a non-stoichiometric solvate where solvent is found in the channels. The solvate is then heated to remove solvent and the resulting spectra are observed, while PXRD patterns showed no differences as the solvent was removed [88].

Figure 13: ¹³C ssNMR of a non-stoichiometric, channel solvate LY297802 tartrate at (a) ambient conditions, (b) elevated temperature with solvent removal, and (c) elevated temperature with increased solvent removal [92].

    
    
    Figure 13:  ¹³C ssNMR of a non-stoichiometric, channel solvate LY297802
tartrate at (a) ambient conditions, (b) elevated temperature with solvent
removal, and (c) elevated temperature with increased solvent removal [92].

Dynamic Vapor Sorption (DVS) is another valuable tool in analyzing pharmaceutical solvates. This instrument measures the mass of a sample with respect to changes in Relative Humidity (RH). For example, if a hydrate-forming API is put into an environment of increasing humidity, a change in mass is seen during hydrate formation. The additional mass will correspond to the ratio of water incorporated into the system, and the graph will form a hysteresis such as the one shown in Figure 14 [89]. This technique can also be used with other organic vapors to determine solvate formation [90]. Solvates that can form in multiple ratios or non-stoichiometrically will show multiple hysteresis. If solvate is found to bind only to the surface, it is easily removed and usually appears as a linear increase in mass with increasing RH [91]. Solvent that is incorporated into the crystal lattice will not instantly be removed; this is illustrated in Figure 14, as well. Once the solvate has formed, it takes a significant decrease in humidity to remove it from the lattice.

Solution NMR is not a useful technique to determine the amount of solvent present due to contaminations. Often the solvate is a hydrate, and water is found in many deuterated solvents [92]. A more appropriate method is to use thermal analysis such as DSC and TGA (thermogravimetric analysis). DSC will show the removal of solvent as an endothermic peak. Due to intermolecular interactions, solvent will evaporate above its boiling point. Channel solvent is usually removed much easier and closer to boiling temperatures. TGA monitors the weight loss as a substance is heated. The percentage lost (assuming the API has not decomposed) will correspond to how much solvent has been removed, which can then be used to calculate the ratio of sovent: API [93].

Excipient Selection and Solid-state Screening

There are a variety of methods to improve the solubility and dissolution rate of APIs; polymorphic screening, salt formation, solvate formation, eutectics formation, co-amorphization, co-crystal formation with an excipient, and co-crystal formation with a second API. In this section, the emphasis is based on the excipient selection. The excipient that is chosen for inclusion into a drug’s solid-state should increase the solubility and consequently the bioavailability of the drug. This is mainly done by choosing molecules that are watersoluble and have plenty of potential for intermolecular bonding [94]. It is also ideal to pick an excipient with a melting point lower than the API for reasons previously mentioned. The principal approach used in choosing an appropriate molecule is the supramolecular synthon method, which evaluates the potential intermolecular bonds between separate constituents of the multi-component solid-state [95]. Illustrated in Figure 15 are both hetero- and homosynthons: one involving a bond that interacts with the same type of bond (e.g. carboxylic-carboxylic) and the latter being dissimilar bond types interacting with each other (e.g. carboxylic-amide). It was reported that heterosynthons are more energetically stable; however, homosynthons are still a feasible means of intermolecular bonding [96]. The proposed intermolecular bonding should be strong enough to displace the bonding of the single components with themselves in order to synthesize the aforementioned solid-states.

Figure 14: Hysteresis shown for an API with the capability to form a solvate. Relative humidity is increased gradually and then reduced [89].

    
    
    Figure 14:  Hysteresis shown for an API with the capability to form a solvate.
Relative humidity is increased gradually and then reduced [89].

A database of approved excipients is easily accessible from the FDA [97], Table 5 is an example of the results for the molecule Ethylparaben (EPB). This excipient is pre-approved for use in drugs both orally and topically with potency varying depending on the method administered. If, for example, to form a co-crystal between an API and EPB, it should be in a ratio that will not cause EPB to be administered more than ~0.6mg per dose.

Table 5: Inactive Ingredient Search for Approved Drug Products, EPB.




  
    Inactive Ingredient 
    Route 
    Dosage Form 
    CAS Number 
    UNII 
    Maximum Potency 
  
  
    Ethylparaben 
    Oral 
    Granule, For Oral Solution 
    120478 
    14255EXE39 
    0.6mg 
  
  
    Ethylparaben 
    Oral 
    Powder, For Oral Solution 
    120478 
    14255EXE39 
    0.66mg 
  
  
    Ethylparaben 
    Oral 
    Powder, For Solution 
    120478 
    14255EXE39 
    0.6mg/2g 
  
  
    Ethylparaben 
    Oral 
    Solution 
    120478 
    14255EXE39 
    0.6mg/5 mL 
  
  
    Ethylparaben 
    Oral 
    Suspension 
    120478 
    14255EXE39 
    2mg/5 mL 
  
  
    Ethylparaben 
    Topical 
    Emulsion, Cream 
    120478 
    14255EXE39 
    NA



Table 5: Inactive Ingredient Search for Approved Drug Products, EPB.

Type of Conclusion	Definition
1	There is no evidence in the available information on [substance] that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when they are used at levels that are now current or might reasonably be expected in the future.
2	There is no evidence in the available information on [substance] that demonstrates a hazard to the public when it is used at levels that are now current and in the manner now practiced. However, it is not possible to determine, without additional data, whether a significant increase in consumption would constitute a dietary hazard.

3	While no evidence in the available information on [substance] demonstrates a hazard to the public when it is used at levels that are now current and in the manner now practiced, uncertainties exist requiring that additional studies be conducted.

4	The evidence on [substance] is insufficient to determine that the adverse effects reported are not deleterious to the public health should it be used at former levels and in the manner formerly practiced.

5	In view of the almost complete lack of biological studies, the Select Committee has insufficient data upon which to evaluate the safety of [substance] as a [intended use].