Solid State Chemistry Of Most Compounds Biology Essay


The solid state chemistry of most compounds is of significant importance to the drug industry. One compound can exist in one or more forms such as salts, polymorphs, solvates, hydrates, co-crystals and amorphous solids. Different solid forms exhibit different physiochemical properties, thus understanding the solid state of an active pharmaceutical ingredient (API) is essential for optimization of drug dosage form design. For the past decades, many APIs in pharmaceutical products have been developed as salts, polymorphs, solvates and amorphous solids. A salt is a neutral compound which arises from ionization between an acid and a base. APIs that are poorly water soluble, free acid or base can be formulated as salts to increase solubility in body fluid hence absorption in body fluid and bioavailability of the drug. The salts are then crystallized.(1) Erythromycin propionate is the salt form of erythromycin which has higher absorbtivity from the gastrointestinal tract and also being less soluble it can avoid from being excessively degraded.(2)

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Crystal form is still one of the main interests in dosage form design which will be discussed in this report. Crystals are highly ordered and structured form of molecules or atoms linked by non-covalent bonds where the free energy is at minimum. The structural units, also named as unit cells are the fundamental repeating building blocks of crystals. There are same amount of molecules, atoms or ions arranged in the same way in each unit cell. Unit cells are repeated indefinitely with a defined orientation in the three dimensional structure of a crystal. The dimensions of the unit cell can be represented by the side lengths a, b and c with angles in between represented by α, β and γ.(3, 4) All possible crystal structures can be one of the seven basic crystal systems, namely cubic, triclinic, hexagonal, tetragonal, orthorhombic, monoclinic and triclinic. Most drugs have triclinic, monoclinic and orthorhombic types of unit cells.(3) Seven crystal systems make up to 14 possible Bravais lattices and 230 space groups. Space group describes the symmetry of molecular arrangement within the unit cell.(4) When crystalline solids of same chemical compound have different molecular packing arrangements, they are known as polymorphs. Polymorphs are chemically identical. Different packing arrangements result in different cohesive packing energies hence different physiochemical properties such as solubility, density and melting point.(4) Different solubility leads to different dissolution rate and bioavailability.(1) Since polymorphs have different lattice energies, the most stable polymorph has the lowest free energy and highest melting point while the less stable, also termed metastable forms will transform into the most stable form at its own rate.(2) An example of polymorphism showed by a drug is paracetamol. Paracetamol is known to crystallize into three polymorphic forms which are monoclinic (form I), orthorhombic (form II) and form III. Form I is more thermodynamically favorable but unsuitable to be manufactured into tablets by direct compression due to poor compressibility. Form II can undergo plastic deformation upon compaction better attributed to its good compressibility, suggesting it being advantageous in tablet manufacturing. In contrast, form III is very unstable and difficult to be isolated thus formulation properties remain unknown.(4, 5) Therefore, selection of polymorph for manufacturing drug products is important for optimum drug activity. Crystals also exist as solvates, also termed pseudopolymorphs. Solvates are formed when compounds crystallize and solvent molecules are entrapped in the crystal lattice in stoichiometric or non-stoichiometric proportions, resulting in their unique physiochemical properties.(6) When water is the solvent incorporated in the crystal, the solvate is also known as hydrate. Solvates are chemically different from polymorphs and similar to co-crystals as both are adducts except that one of the component of solvate is liquid and for co-crystal is solid.(7) Theoretically, adducts are easier to crystallize because two molecules can stack together better possibly due to symmetry, conformation changes induced by adduct and ability to form hydrogen bonds.(4) Since solvates can crystallize more easily and spontaneously, the resultant crystal is often of lower free energy leading to lower solubility.(7) Solvation also depends on the activity of the solvent and interaction between the solvent and drug molecules.(8) Taking theophylline as example, it can form solvate with water forming theophylline monohydrate.(3) Desolvation occurs when the solvent molecule is lost but the crystal lattice remains. Desolvation of a crystalline solvate may give rise to a range of polymorphs or an amorphous material depending on the desolvation method used. Recently, co-crystal is being introduced into pharmaceutical field for its wide range of benefits such as enhanced solubility, bioavailability, stability and hygroscopicity. Co-crystals are mixtures of two solid components linked by non-ionic and non-covalent bonds.(9) For example, succinic acid co-crystal of fluoxetine hydrochloride was shown to have improved dissolution rate.(10)

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Amorphous or glassy soilds are in contrast to crystalline solids because they do not have long range order molecular packing and a well-defined conformation. Thus, amorphous solids are not crystalline and also known as disordered and frustrated systems. However they may have short range molecular order that are similar to crystalline solids.(11, 12) Amorphous solids have always been an interest to pharmaceutical industry as they offer some advantages over crystalline solids in certain conditions. APIs that are difficult to crystallize can be produced in their amorphous form when crystal forms are not available. Amorphous atorvastatin is an example of a drug developed in amorphous form as the crystalline form is not available.(7) Due to their high energy, amorphous solids generally have higher solubility, dissolution rate, better compressibility and can be produced under standard chemical processes. The main concern of developing amorphous compounds is their thermodynamic instability and lack of characterization tools.(7, 11, 12) The best way to characterize amorphous compounds is by its glass transition temperature (Tg) where the compound is kinetically unable to achieve equilibrium and loses it thermal energy. When heated above the Tg , an amorphous solid will change from its glassy state into a fluid-like rubbery state. This will lead to enhanced chemical reactivity, reduced stability and spontaneous crystallization with reduced solubility.(6, 12) There are various solid forms available, each with its distinct properties typically solubility and melting point which have profound effects on drug activity. Therefore, proper understanding of the solid states is crucial for selection of solid state forms for development of drug products.

The most general and effective method of producing crystalline API is crystallization from solution or from the melt.(8) Crystallization method regulates the crystalline form, size and habit of the crystal.(4) Crystallization from solution is basically resulted from supersaturation, crystal nuclei formation and crystal growth. Supersaturation is commonly achieved by cooling, evaporation, vacuum, chemical reaction or addition of precipitant.(13) It is also known as non-equilibrium method due to rapid variation in temperature, drying and solvent exchange.(8) Examples of pharmaceutical products from crystallization by cooling are suppositories and cream.(2) However, supersaturation itself is inadequate to form crystal as crystal nuclei are result of collision between drug molecules in solution to form aggregation. Nucleation may take place randomly or induced by purpose. Agitation, friction, mechanical shock and extreme pressure can cause nuclei formation in solution and melt.(13) Sometimes seed crystals or foreign particles are added to induce nucleation. After nucleation, crystal nuclei will then grow into macroscopic crystal.(3, 4) An equilibrium method of crystallization from solution is based on evaporation of solvent at a constant concentration in equilibrium with the crystal.(8) Crystallization from the melt uses liquid at a condition that is close to its melting point. It is mainly a controlled cooling crystallization process and is beneficial in processing APIs that are thermodynamically unstable as it is carried out at a lower temperature. However, the downside of the need of isolating the purified APIs from impurities and cost of refrigeration outweigh the benefits.(13)

Many factors need to be considered during crystallization including temperature, pressure, pH, extent of agitation, degree of supersaturation and nature of solvent. Temperature and pressure are crucial in defining an API's stability and solubility. Selection of crystallization condition mainly depends on the temperature and pressure.(8) One of the problems in developing drugs particularly in mixing, dissolution, tableting and injection is crystal habits as crystals may have different shapes.(3, 7) Besides that, phase transitions may occur during various stages of drug development posing a problem to pharmaceutical industry. This could be due to interconversion between polymorphs, solvate desolvation, hydrate formation and change in degree of crystallinity which in turn change the bioavailability of the drug.(4) Phase transformation might alter the crystal habit, thermodynamic properties of the drug and consequently its dissolution and bioavailability.(2) Various pharmaceutical processes may have significant influence on the final crystalline form of a drug. An amorphous compound can crystallize into a more stable crystalline form when there is sufficient molecular mobility. This can be seen in pharmaceutical processes such as spray and freeze drying, supercooled melts and during storage especially when exposed to high temperature and humidity.(11) Spray drying and lyophilization might also alter the drug into its amorphous form which can be less stable and more hygroscopic. Stresses applied on drug during grinding, milling, granulation, drying and compaction also tend to accelerate phase transitions. Degree of transformation depends on the stability of the phases and stresses applied.(2, 4) For example, polymorph transformation might occur in digoxin during milling. Granulation might form solvate and drying might cause a solvate transforms into anhydrous form.(2) Therefore, the US Food and Drug Administration (FDA) stresses the importance of using appropriate analysis for detection of polymorphs, solvates, amorphous solids and to control the crystal form of the drug.(4, 11)

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Various techniques are available for analysis and characterization of solid states of APIs. All techniques vary in their principles, duration of analysis and amount of sample needed, sensitivity and specificity.(12) Selection of analytical techniques may depend on the instrument availability, cost, time and nature the material. If possible, a reliable list of polymorphs with their stabilities and transition points should be obtained due to economic concern.(14) Common techniques that are used include X-ray powder diffraction (XRPD) and single crystal X-ray diffractometry, hot stage microscopy, infrared (IR) spectroscopy, differential scanning calorimetry/ thermogravimetric analysis (DSC/TGA), nuclear magnetic resonance (NMR) spectroscopy, solubility and dissolution tests.(4, 14)

Diffraction techniques can be considered the best method to detect and quantify any system's molecular order.(12) As all polymorphs and solvates have different crystal packing, they can be distinguished by these techniques through their unique diffraction pattern. Single crystal X-ray diffractometry is one of the most powerful method in identifying the molecular and crystal structure of an API and its polymorphs and solvates.(4) It defines the unique packing of molecules, interconnection between molecules and the molecular conformation in crystal lattice. However it is often difficult to produce crystal of sufficient size for single crystal analysis especially when unstable and enantiomeric polymorphs are involved.(14) XRPD is one of the most widely used methods as powder patterns are much easier to be obtained due to its simplicity.(12) It gives the' fingerprint' of the crystal and can also be used to determine the crystal structure.(4) Besides that, XRPD can be used to detect subtle differences in samples that cannot be detected by microscopy, thermal analysis or spectroscopy.(14) XRPD is also used to identify amorphous compounds down to 5% level and able to study phase transformation by controlling the temperature and environment. On top of that, it can distinguish between a pure crystalline sample and a mixture of crystalline and amorphous sample and quantify them. A problem encountered with large crystals samples in XRPD is these may give spotty patterns, making it hard to produce line intensity measurements and for comparison with other samples' diffractograms. This problem can be overcome by grinding and suitable presentation provided the polymorph is stable. Inert powder can be added for soft crystal to assist grinding.(14) XRPD is also unsuitable for samples with complex scattering patterns as isolation of peaks could be difficult.(12)

Once a polymorph or solvate has been confirmed by diffraction, other techniques can be used for further characterization. Quantification can be done by thermal analysis. Main thermal analytical techniques that are used are DSC and TGA which are combined in one instrument as simultaneous thermal analysis (STA). STA simply means simultaneous application of different thermal analysis. The sample is heated and cooled in a single furnace. Advantages of using STA are shorter time is required to perform all measurements, accurate correlation of the observed events, synergistic effect in the information collected from the sample and a more constant result as same sample is used for different techniques but under same external factors.(15) STA also distinguishes processes including desolvation, sublimation, recrystallization and decomposition from pure phase changes. It could also be used to calculate the ratio of each solvate.(6, 14) TGA is used to measure changes in a sample mass with temperature thus it is particularly useful in identifying solvent loss. Since STA records dynamic processes, changes in temperature, heating condition and sample environment may affect the processes.(14) DSC is used to investigate phase behavior of the samples and quantification of amorphous samples.(12) Thermograms obtained from DSC may be affected by rate of heating, sample packing, crystal size, atmosphere and encapsulation.(14) Polymorphs often will transit to another polymorph with higher melting point when heated slowly at the transition temperature but will remain at its own melting point when heated rapidly. To investigate melting point, small amount of samples are adequate and the melting point will be shown as the maximum peak.(14) Analysis should be done using an open or pin-prick pan to allow escape of solvent.(6)

Microscopy is an outstanding method to visualize crystals. Sometimes a pre-examination using binocular microscope will be done to confirm the overall structure of the sample. Further characterization using hot stage-polarizing microscope enables determination of transition points, sample tendency to melt and phases to supercool, stable and unstable polymorphs and optical properties. There might be observation of solvation, sublimation and decomposition. Benefit of this technique is only a small amount of sample is required.(14)

Spectroscopy is a high resolution technique used to identify polymorphs, solvates and amorphous solids from the motions of the functional groups and the molecular identity.(14, 16) Main purpose of this technique is to study the structural aspects which give rise to differences in crystallinity. High quality IR spectra is best obtained from Fourier Transform IR (FTIR) technique.(16) The absorbed polarized radiation is studied to understand the orientation of the molecules.{THRELFALL, 1995, ANALYSIS OF ORGANIC POLYMORPHS - A REVIEW}(14) Samples can be distinguished from their mid-IR ('fingerprint') region as each compound will show distinctive absorption bands patterns. Even minute differences in the peak positions, shapes, presence or absence of bands can be used for characterization.(14) Degree of crystallinity is measured by looking at the intensity of a peak with reference to a control peak. The intensity of the vibrational bands produced by the sample is proportional to the concentration of the phase being studied.(12) Fourier Transform Raman spectroscopy (FTRS) is an alternative which measures inelastic scattering of radiation with loss of vibrational energy. Notch filter is often used to eliminate excitation lines to acquire a good radiation.(14, 16) The differences between FTIR and FTRS are that IR vibration is based on changes in molecular dipole while Raman vibration is based on changes in polarizability, Raman spectra tend to show narrower bands compared to IR spectra and IR spectra can be affected by neighbouring molecules through hydrogen bonding and spatial distance effect. Thus, conformational polymorphism would be more distinct in Raman spectra while packing effects of hydrogen bonding molecules and such would be more observable in IR spectra. Advantages of FTRS over FTIR are sample manipulation is not required hence it is non-destructive, rapid data collection without removing sample from sample tube and minimal interference from water. The downside of FTRS is that spectra cannot be recorded at very low frequencies thus differences between polymorphs at that region cannot be detected.(12, 14) NMR spectroscopy is probably the best method for characterization down to the level of individual atoms.(16) By using proper pulse-sequence techniques, carbon type can be assigned at solid state to interpret molecular structure or the spectra of interest is compared with solution spectrum.(14) It is used for studying crystals, amorphous solids and pharmaceutical dosage forms by illustrating hydrogen bonding and molecular conformation of polymorphs. This technique is particularly useful in conformational polymorphism in origin when the single crystal structures are not available. Various molecular environments of nuclei in solvates can be studied as well.(4, 16)

Characterization of polymorphs can also be done using solubility and dissolution techniques. Solubility is one of the main properties of polymorphs in developing drug dosage form. It is related to stability where the most stable polymorph is always least soluble. By carrying out solubility test over a range of temperature, polymorph transition points and thermodynamic stability can be understood.(14) Dissolution can be considered as the rate limiting step in drug absorption. Increased dissolution rate is favored for increased bioavailability. To carry out the test, the solid is dispersed in dissolution medium and crystallinity is quantified from the amount dissolved. A few concerns with this method are that surface area need to be controlled and appropriate selection of dissolution medium.(12) Analysis can also be done using ultraviolet (UV) and fluorescence techniques. Limited structural information is gained from UV spectroscopy but a major strength of this technique is measuring equilibrium solubility of a range of forms for a given API. Relative ranked solubilities provide a ranking of relative stability.

The work presented here focuses on physical form screen and analysis of bendroflumethiazide (BFMTZ). BFMTZ or 3-benzyl-6-(trifuoromethyl)-3,4-dihydro-

2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide is a thiazide diuretic drug used to treat hypertension and oedema. It was firstly synthesized by Holdrege, Babel and Cheney in 1959. BFMTZ appears as white, free-flowing crystalline powder with a very light floral odor. Chemical structure of BFMTZ is C15H14F3N3O4S2 with a molecular weight of 412.41g/mol.(17) There is no crystal structure of anhydrous BFMTZ in the literature. Up to date, only two forms of BFMTZ have been discovered which are BFMTZ acetone solvate, C15H14F3N3O4S2•C3H6O and BFMTZ N,N-dimethylformamide (DMF) solvate, C15H14F3N3O4S2•C3H7NO both at a ratio of 1:1 (Table 1).(18)

BFMTZ acetone solvate

BFMTZ DMF solvate

Chemical formula







8.192 Å

8.2527 Å


9.525 Å

17.8431 Å


14.101 Å

14.9012 Å


99.538 Å


100.171 Å

103.752 Å


100.42 Å

2131.35 Å

Table 1: Crystal data of BFMTZ solvates(18)

The aim of this research is to perform a physical form screen of BFMTZ and to obtain as much information as possible of the solid state behaviour of this compound. Objectives are outlined as below:

Crystallize BFMTZ from solution using a range of solvents and to distinct crystallization conditions for each solvent.

Characterize each recrystallized sample using XRPD as a primary tool of analysis.

Perform complementary analytical methods on recrystallized samples such as STA to determine if forms are solvates or anhydrous, single crystal X-ray diffraction to determine crystal structure and microscopy to assess morphology across a range of forms.

Correlate results of crystallization outcome with condition.