PHAR 214 Pharmaceutical Engineering I

Unit- 7: Crystallization
Achyut Bikram Thapa

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Duration of study: 5 hours

1. Theory and application, 2. Characteristics of crystals (geometry, habit, crystal lattice, crystal systems), 3. Pharmaceutical solids (crystalline, amorphous,) 4. Polymorphs and isomorphs, 5. Crystal hydrate and caking of crystals. 6. Crystal hydrates and crystal solvates, 7. Production of very fine crystals, 8. Production of large crystals. 9. Crystallizers (Agitated batch crystallizers, Swenson Walker Crystallizer, Krystal Crystallizer, vacuum crystallizer).

Solid state and solid substances

Solids are characterized by incompressibility, rigidity and mechanical strength. Molecules, atoms or ions that make up a solid are closely packed and held together by strong forces.

Based upon the arrangement of molecules, atoms or ions, solids may be of two types a. amorphous solid b. crystalline solid

Solid state and solid substances

Amorphous solid An amorphous solid is a substance whose constituent units do not posses an orderly arrangement over a long range. These are sometimes referred to as super cooled Liquids due to disorderly arrangement like liquids.

Crystalline solid
Crystals contain highly ordered arrays of molecules and atoms held together by non-covalent interactions. Within a specific crystal, each unit cell is the same size and contains the same number of molecules or ions arranged in the same way. It is usually most convenient to think of the atoms or molecules as points and the crystal as a three dimensional array of these points, or a crystal lattice. Crystalline solids are in a form of definite geometric pattern.

Differences between amorphous and crystalline solids 1. Geometric shape due to definite and regular arrangement or molecules, atoms or ions in 3-D space crystals bear definite geometry. Amorphous solids dont have definite geometrical shape.

2. Melting point Crystals have sharp MP i.e. changes abruptly into liquid state at a fixed temperature. Amorphous solids dont have sharp MP and phase change is not abrupt.
3.Isotropy Crystalline solids are anisotropic i.e. their physical properties like refractive index, thermal and electrical conductivity are different in different direction.

Differences between amorphous and crystalline solids Anisotropy is a strong evidence for the existence of ordered arrangement in such materials. Amorphous solids are isotropic i.e. their physical properties are same in all directions. 4. Cleavage Crystals are cleaved along preferred direction with plane surface. Amorphous solids on cleavage results irregular surface.

Crystal lattice In crystalline solids, the constituent units, atoms, molecules or ions are arranged in a regular repeating pattern in 3D region called as crystal lattice. It is constructed from repeating units called unit cell. A unit cell is the smallest repeating unit in a crystal lattice which when repeated again and again in different directions results in the crystal of the given substance. All unit cells in a specific crystal are the same size and contain the same number of molecules or ions arranged in the same way.
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Crystal lattice

A crystal is bounded by plane surface called faces. The angle between the two perpendicular to the intersecting faces is termed as axial angle. Distance between the center of two atoms is called axial length.
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Crystal unit cell

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Crystal unit cell

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Crystal unit cell

The structures of unit cells have atoms or molecules only at each corner of the unit cell. It is possible to find unit cells with atoms or molecules also at the centre of the top or bottom faces (end-centered), at the centre of every face (face-centered) or with a single atom in the centre of the cell (body-centered). Note that these variations do not occur with every type of unit cell. we find End-centered monoclinic and orthorhombic Face-centered cubic and orthorhombic Body-centered, cubic, tetragonal and orthorhombic.
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Crystal unit cell There are therefore only 14 possible types the Bravais lattices.

Drug molecules usually have triclinic, monoclinic or orthorhombic unit cells.

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Isomorphism In crystallography crystals are described as isomorphous if they are closely similar in shape. Historically crystal shape was defined by measuring the angles between crystal faces with a goniometer. In modern usage isomorphous crystals belong to the same space group.
In order to form isomorphous crystals two substances must have the same chemical formulation, they must contain atoms which have corresponding chemical properties and the sizes of corresponding atoms should be similar. These requirements ensure that the forces within and between molecules and ions are approximately similar and result in crystals that have the same internal structure. Even though the space group is the same, the unit cell dimensions will be slightly different because of the different sizes of the atoms involved.
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Polymorphism The arrangement of molecules in two or more different ways in the crystal; either they may be packed differently in the crystal lattice (packing polymorphism)or there may be differences in the orientation or conformation of the molecules at the lattice sites (conformational polymorphism) is termed as polymorphism. These variations cause differences in the X-ray diffraction patterns of the polymorphs and XRD is one of the main methods of detecting the existence of polymorphs.
Polymorphs of a given compound have different physicochemical properties, such as melting point, solubility and density, so that the occurrence of polymorphism has important formulation, biopharmaceutical and chemical process implications. 15

Polymorphism
Spironolactone, a diuretic steroidal aldosterone agonist, crystallises as two polymorphic forms depending on the solvents and methods used for crystallisation. Form 1 is produced when spironolactone powder is dissolved in acetone at a temperature very close to the boiling point and the solution is then cooled within a few hours down to 0C. Form 2 is produced when the powder is dissolved in acetone, dioxane or chloroform at room temperature and the solvent is allowed to evaporate spontaneously over a period of several weeks.

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Polymorphism
Paracetamol is known to exist in two polymorphic forms, monoclinic (Form 1) and orthorhombic (Form 2), of which Form 1 is the more thermodynamically stable at room temperature and is the commercially used form. However, this form is not suitable for direct compression into tablets and has to be mixed with binding agents before tableting, a procedure that is both costly and timeconsuming.

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Polymorphism Form 2 polymorph can readily undergo plastic deformation upon compaction and it has been suggested that this form may have distinct processing advantages over the monoclinic form. Monoclinic paracetamol is readily produced by crystallisation from aqueous solution and many other solvents; production of the orthorhombic form has proved more difficult but may be achieved, at least on a laboratory scale, by nucleating a supersaturated solution of paracetamol with seeds of Form 2 (from melt-crystallised paracetamol).
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Polymorphism
Crystal structures containing solvents (or water) are often called Pseudopolymorphs. Polymorphs and pseudopolymorphs can also be classified as 1. Monotropes 2. Enantiotropes, This is based upon whether or not one form can transform reversibly to another.

1. Monotropic system/ Monotropes Form I does not transform to Form II, because the transition temperature cannot appear before the melting temperature.
The change between the two forms is irreversible.
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Polymorphism 2. Enatiotropic system/ Enantiotropes one polymorph can be reversibly changed into another one by varying the temperature or pressure.
Form II is stable over a temperature range below the transition temperature, at which two solubility curves meet, and Form I is stable above the transition temperature. At the transition temperature, reversible transformation between two forms occurs.

Monotropes as function of temperature

20 Enatiotropes as function of temperature

Polymorphism

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Pharmaceutical implication of polymorphism Different crystal habits, crystal lattices and consequently their energy contents of polymorphs are sufficiently different to influence their stability and biopharmaceutical behavior. For drugs with more than two polymorphs we need to carry out this experiment on successive pairs of the polymorphs of the drug until we eventually arrive at their rank order of stability. Stability of polymorphs are determined by a simple experiment in which the polymorphs are placed in a drop of saturated solution under the microscope. The crystals of the less-stable form will dissolve and those of the more stable form will grow until only this form remains.
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Pharmaceutical implication of polymorphism 1. Transformations The transformation between polymorphic forms can lead to formulation problems. -Phase transformations can cause changes in crystal size in suspensions and their eventual caking. -Crystal growth in creams as a result of phase transformation can cause the cream to become gritty. -Changes in polymorphic forms of vehicles, such as theobroma oil used to make suppositories, could cause products with different and unacceptable melting characteristics.

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Pharmaceutical implication of polymorphism 2. Analytical issue Differences in melting points, solubilities and infrared spectra of polymorphs create problem for analytical work. Changes in infrared spectra of steroids due to grinding with potassium bromide (KBr) have been reported; changes in the spectra of some substances have been ascribed to conversion of a crystalline form into an amorphous form (as in the case of digoxin), or into a second crystal form. Changes in crystal form can also be induced by solvent extraction methods used for isolation of drugs from formulations prior to examination by IR spectroscopy. Difficulties in identification arise due to polymorphism.
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Pharmaceutical implication of polymorphism 3. Bioavailabilty The most stable polymorph usually has the lowest solubility and slowest dissolution rate and consequently a lower bioavailability than the metastable polymorph. Fortunately, the difference in the bioavailability of different polymorphic forms of a drug is usually insignificant.

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Pharmaceutical implication of polymorphism

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Crystal hydrates and solvates When some compounds crystallize they may entrap solvent in the crystal. Crystals that contain solvent of crystallization are called crystal solvates. When water is the solvent of crystallization it is termed as crystal hydrates . Crystals that contain no water of crystallization are termed anhydrates or anhydrous crystals. Behavior of crystal solvates varies depending on the interaction between the solvent and the crystal structure.

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Crystal hydrates and solvates Polymorphic solvates These are very stable and are difficult to desolvate because the solvent plays a key role in holding the crystal together and it may be part of a hydrogen-bonded network within the crystal structure. When these crystals lose their solvent they collapse and recrystallize in a new crystal form. Pseudopolymorphic solvates The solvent is not part of the crystal bonding and merely occupies voids in the crystal. These solvates lose their solvent more readily and desolvation does not destroy the crystal lattice.
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Crystal hydrates and solvates Spironolactone, has two polymorphic forms and possesses four solvates, depending on whether it is crystallized from acetonitrile, ethanol, ethyl acetate or methanol. Each of these solvates is transformed to the polymorphic Form 2 on heating, indicating that the solvent is involved in the bonding of the crystal lattice.

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Crystal hydrates and solvates

The solvated forms of a drug have different physicochemical properties to the anhydrous form:

Melting point of the anhydrous crystal is usually higher than that of the hydrate. Anhydrous crystals usually have higher aqueous solubilities than hydrates. The rates of dissolution of various solvated forms of a drug differ but are generally higher than that of the anhydrous form. There may be measurable differences in bioavailabilities of the solvates of a particular drug.
For example, the mono ethanol solvate of prednisolone tertiary butyl acetate has an absorption rate in vivo which is nearly five times greater than that of the anhydrous form of this drug.
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Crystal hydrates and solvates

Although solvates can show higher solubilities and dissolution rates compared to non-solvated species, solvates cannot normally be used in the pharmaceutical arena. Residual solvents have been classified by the ICH into three classes:

1. Class I solvents: Solvents to be avoided.

includes known human carcinogens, strongly suspected human carcinogens and environmental hazards, e.g., benzene, carbon tetrachloride and 1,2 dichloroethane.

2. Class II solvents: Solvents to be limited

These include non-genotoxic animal carcinogens or possible causative agents (e.g., acetonitrile, cyclohexane, toluene, methanol and N,N-dimethylacetamide) of irreversible toxicity such as neurotoxicity or teratogenicity. Also included are solvents suspected of other significant but reversible toxicities.
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Crystal hydrates and solvates 3. Class III solvents: Solvents with low toxic potential
acetic acid, acetone, ethanol, ethyl acetate and ethyl ether. Also included are solvents with low toxic potential to man are also included here; no health-based exposure limit is needed. Class III solvents have permissible daily exposures (PDEs) of 50 mg or more a day. It is important that solvates are desolvated before use. Usually vacuum drying is used Because of toxicity or potential toxicity, use of solvates is not encouraged. But, it is interesting to note that according to Glaxos British patent 1,429,184, the crystal form of beclomethasone dipropionate used in the MDI is the trichlorofluoromethane solvate. By using the solvate, it was found that crystal growth due to solvation of the propellant chlorofluorocarbon (CFC) was prevented. 32

Crystallization
Crystallization is the (natural or artificial) process of formation of solid crystals precipitating from a solution, melt or more rarely deposited directly from a gas. It is a chemical solidliquid separation technique, in which mass transfer of a solute from the liquid solution to a pure solid crystalline phase occurs. It is an aspect of precipitation, obtained through a variation of the solubility conditions of the solute in the solvent, as compared to precipitation due to chemical reaction.
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Theory of crystallization
Although size of the material and pressure plays little role , solubility mainly depends on temperature. Solubility data plotted in the form of curves where solubility are expressed against temperature i.e. solubility curve give a better picture of behavior of the material in a crystallization process.
Solubility curve of some solids and gases
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Theory of crystallization
Crystallization from solution can be considered to be the result of three successive processes: Supersaturation of the solution Formation of crystal nuclei Crystal growth round the nuclei Supersaturation of the solution Super saturation is the driving force of the crystallization. This can be achieved by - cooling, - evaporation, - addition of a precipitant or - a chemical reaction that changes the nature of the solute. 35

Theory of crystallization
Formation of crystal nuclei:
Supersaturation itself is insufficient to cause crystals to form; the crystal embryos must form by collision of molecules of solute in the solution, or sometimes by the addition of seed crystals, or dust particles, or even particles from container walls. Deliberate seeding is often carried out in industrial processes; seed crystals do not necessarily have to be of the substance concerned but may be isomorphous substances (i.e. of the same morphology). As soon as stable nuclei are formed, they begin to grow into visible crystals. when the clusters are not stable, they re-dissolve. Therefore, the clusters need to reach a critical size in order to become stable nuclei. Such critical size is dictated by the operating conditions. Nuclei may continue to form while other nuclei are already 36 present and growing.

Theory of crystallization
Crystal growth round the nuclei: Crystal growth is the subsequent growth of the nuclei that succeed in achieving the critical cluster size. Nucleation and growth continue to occur simultaneously while the super saturation exists. Depending upon the conditions, either nucleation or growth may be predominant over the other, and as a result, crystals with different sizes and shapes are obtained. Once the super-saturation is exhausted, the solid-liquid system reaches equilibrium and the crystallization is complete.

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Theory of crystallization

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Miers Supersaturation Theory

AB- normal solubility curve FG- super solubility curve

If a solution having the composition and temperature of point C is cooled in the direction of CD, it first crosses the 39 solubility curve and crystallization is expected.

Miers Supersaturation Theory

However, if the solution is free from all types of solid particles, the solution will not begin to crystallize until it has supercooled considerably past the curve AB. According to Meirs supersaturation theory, somewhere in the neighborhod of point D, crystallization begins and the concentration of the substance in solution then roughly follows curve DE. The super solubility curve FG represents the limit at which nucleus formation begins spontaneously and crystallization can start. At any point along the line CD, nuclei formation cant take place and no crystallization occurs.
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Conditions for Miers Supersaturation Theory

1. 2. 3. 4. 5. 6. Solvents must be pure Free from solid solute particles Free from foreign solid materials Free from entry of any dust particles Soft crystals shouldnt form during the process Should not be any fluctuation in temperature

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Limitation of Miers Theory

It is better to consider the critical supersolubility range not as a definite line but as an area. If sufficiently long time is given, nuclei can form well below the supersolubility curve. If the nucleus formation depends upon accidental collision of solute molecules, it is possible that the larger the volume of the solution the greater is the chance for such collision. This process was actually found true. As long as the nucleus formation depends upons accidental combination of the solute molecules to form permanent aggregates, the line FG cannot be drawn.

Foreign solid particles or isomorphic particles act as nuclei. But Miers theory deals only with pure solution comparatively free from every particles of solid matter.

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Limitation of Miers Theory

Long time, large volume of solution and presence of foreign particles or solute particles introduced as dust a conditions for crystallization. The existence of fixed supersolubility curve FG is no longer possible. Greater the degree of supersaturation, the greater is the probability of nucleus formation and the more rapid is the growth of nucleus.

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Thermodynamic drivers of crystallization

The nature of a crystallization process is governed by both thermodynamic and kinetic factors, which can make it highly variable and difficult to control. Factors such as impurity level, mixing regime, vessel design, and cooling profile can have a major impact on the size, number, and shape of crystals produced. Whether considering nucleation or growth, the reason for the transformation from solution to solid is the free energy of the initial solution phase that is greater than the sum of the free energies of the crystalline phase plus the final solution phase.

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Caking of crystals
The tendency of crystalline material to bind or cake together is termed as caking of crystals. Caking is troublesome in bulk storage and in large container but most serious in small packages. The extent of caking may vary from formation of a loose aggregates to solid lumps that have to be crushed with considerable force. As consumer demand a free flowing product, prevention of caking is a serious problem for manufacturer.

Caking is attributable to a small amount of dissolution taking place at the surface of the crystals and subsequent reevaporation of the solvent. The crystals become very tightly bonded together.
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Caking of crystals
If the crystals are large so that there are few points of contact and there is a large free volume between the crystals so there is no appreciable bonding of the crystals, this will lead to caking minimization. If the crystals are fine or have small percentage of voids or are in contact with a moist atmosphere for a long time, sufficient moisture may be absorbed to fill the voids entirely with saturated solution and when this have been reevaporated, the crystals will lock into a solid mass of cake of crystal.

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Caking of crystals
Caking depends upon 1. Vapor pressure of the solution. 2. Relative humidity (partial pressure of water in atmosphere) If a saturated solution is brought into contact with air in which the partial pressure of water is less than the vapor pressure of the solution, the solution will evaporate. On the other hand, if the air contains more moisture than this limiting amount, the solution will absorb water until it is so dilute that its vapor pressure is equal to the partial pressure of the moisture of the air with which it is in contact.
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Caking of crystals
At 70 F, vapor pressure of saturated NaCL solution = 14.63 mm and partial vapor pressure of water = 18 .76 mm. the ratio is fairly constant and called relative humidity

Relative humidity of saturated NaCl solution = (14.63)/ 18.76 x 100 = 77.8% If salt at 70 F is brought into contact with air its relative humidity > 78%, the partial pressure of water vapor in the air is more than that of saturated salt solution so moisture will be absorbed and condensed on the salt.
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Caking of crystals
If NaCl is exposed to air its relative humidity < 78%, it will stay dry, due to evaporation of H2O from the solution and caking doesnt occur. 78% in referred to the critical humidity of NaCI.
Critical humidity is the relative humidity above which the crystals will become damp and below which they will stay dry.

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Prevention of caking
Following conditions are desirable to prevent caking. 1. Maintaining the highest possible critical humidity: Maximum critical humidity is often obtained by removing impurities such as CaCl2 or MgCl2.These impurities have a lower critical humidity than the product desired. Presence of impurities absorb H2O from atmosphere and caking occurs.
2. Uniform crystals with maximum percentage of voids and fewest possible points of contact :
To increase the percent of voids, it is not necessary to produce larger crystals but to produce a more uniform mixture. For a given crystal form and for absolutely uniform sized crystals, the percentage of voids is same irrespective of the crystal size. 50

Prevention of caking
However, non uniformity in particle size rapidly decreases the percent of voids. A fine product has more points of contact per unit volume than a coarse one and hence a greater tendency to cake.
3. Coating of crystals with inert materials: Inert materials like magnesia or tricalcium phosphate or anhydrous CaCl2 can absorb moisture and are used to coat the crystals. But this is not always applicable.

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Types of crystallization
Crystallization may occur naturally or artificially.
Natural crystallization: There are many examples of natural process that involve crystallization. Geological time scale process Mineral crystal formation (gemstone), Stalactite/stalagmite, rings formation. Usual time scale process Snow flakes formation, Honey crystallization (nearly all types of honey crystallize).
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Types of crystallization
Artificial Crystallization
Crystals can be produced artificially by any one of the following processes:

1. Supersaturation by cooling alone

A. Batch crystallizers i. Tank crystallizers ii. Agitated batch crystallizers B. Continuous crystallizers i. Swenson-Walker crystallizer

2. Supersaturation by evaporation of the solvent

i. Krystal crystallizer

3. Supersaturation by adiabatic evaporation i.e. cooling and evaporation/ Vacuum crystallizers

A. without external classifying seed bed B. With classifying seed bed

4. Supersaturation by salting out

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1. Supersaturation by cooling alone

This is applicable for those substances that have a steep solubility curve where the solubility of substance rapidly decreases with reduction in temperature. The solution is generally concentrated in a separate evaporator (but not to saturation) and then fed to the crystallizer. As many substances exhibit this curve, these crystallizers are commonly employed.

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2. Supersaturation by evaporation of the solvent

This method is employed in the crystallization of substances like common salt where the solubility curve is either flat or not too steep and the yield of the solid by cooling alone is negligible.

3. Vacuum crystallizers
This is most important for large scale production. If a hot saturated solution is introduced into a crystallizer in which sufficient vacuum is maintained with the total pressure less than the vapor pressure of the solution at the temperature at which it is introduced, the solution must flash and be cooled by the resulting adiabatic evaporation, thus attaining the desired supersaturation causing crystallization. Apart from cooling the solution, evaporation 55 taking place increases the yield of crystals.

4. Supersaturation by salting out

This is carried out by adding another substance that reduces the solubility of the substances in solution to such an extent that the desired solute separates or crystallizes out of the solution. Salting out with third substance deliberately introduced is rarely employed.

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Agitated batch crystallizer

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Agitated batch crystallizer

Artificial cooling speeds the crystallization and this is the basis for agitated batch crystallizer. Water is circulated though the cooling coils and the solution is agitated by the propellers mounted on the central shaft. Agitation performs two functions: 1. increases the rate of heat transfer and keeps the temperature of the solution more uniform. 2. keeps the fine crystals in suspension, thus it gives them an opportunity to grow uniformly instead of forming large crystals or aggregates. The product of this operation is not only more uniform but it also very much finer than that from the older tanks.
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Disadvantages of agitated batch crystallizer

1. It is a batch or discontinuous apparatus. 2. The solubility is the least at the surface of the cooling coils. Therefore, crystal growth is most rapid at this point and the coils rapidly build up with a mass of crystals that decreases the rate of heat transfer.

Swenson- Walker crystallizer

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Swenson- Walker crystallizer

This is common type of continuous crystallizer using cooling alone to bring about the supersaturation. It consists of an open trough 2 ft. wide and 10ft. long with a semi-cylindrical bottom, a water jacket welded to the outside of the trough. Long pitch spiral agitator at speed of 7rpm is set very close to the bottom of the trough. A number of units may be joined together to give increased capacity. The hot concentrated solution to be crystallized is fed at one end of the trough and cooling water usually flows through the jacket in counter current to the solution. In order to control crystal size, it is sometimes desirable to introduce an extra amount of water into certain 60 sections in the jacket.

Swenson- Walker crystallizer

Functions of the spiral stirrer: 1. It Prevents the accumulation of crystals on the cooling surface. 2. It lifts the crystals that have already been formed and shower them down through the solution. In this manner, the crystals grow while they are freely suspended in the liquid and therefore they are: 1. Fairly perfect individuals. 2. Uniform in size 3. Free from inclusions or aggregations.
At the end of the crystallizer there may be an overflow gate where crystals and mother liquor overflow to a drain box from which the mother liquor is returned to the process and the wet 61 crystals are fed to a centrifuge to remove mother liquor.

Advantages of Swenson- Walker crystallizer

Advantages: 1. Large saving in floor space. 2. Large saving in material in process. 3. Saving in labor. 4. Uniform size crystals. 5. Free from inclusions and aggregations.

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Krystal crystallizer
A: discharge tube to bottom of crystal bed B:Overflow to circulation pump

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Krystal crystallizer
1. Overflow from crystal growth chamber is sent up by circulating pump via heater and is discharged into the vapor head. 2. In vapor head, solution is flash cooled resulting supersaturation. Vapor produced goes to barometric condenser from vacuum pump. The operation of vapor head is controlled such that crystals do not form there. 3. Supersaturated solution after flashing passes into crystallizing chamber via discharge tube extended to the bottom of the chamber. The chamber contains a bed of crystals suspended in an upward flowing stream of liquid caused by discharge from discharge tube. 4. The overflowing fine crystal suspension is heated in the 64 heater and crystals go into solution.

Krystal crystallizer
5. The process is repeated and larger crystals are drawn from the product discharge. 6. In this crystallizer, gradation of crystals occur. Coarse crystals are seated at bottom and finer at the top of the layer and finest ones overflow as suspension that is circulated by pump.

In this apparatus, larger crystals can be produced by controlling various parameters like supersaturation in the liquid coming from the vapor head. Production of larger crystals however is costly affair as too many fine crystals produced must be re-dissolved.
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Vacuum crystallizer without external classifying seed bed This crystallizer is cone bottomed vessel with feed of hot saturated solution form the top. Use of highly efficient steam jet ejector produces a high vacuum resulting to the flashing of the feed solution and consequent adiabatic cooling produces low temperature enabling large yield with minimum amount of mother liquor returning to the system.66

Vacuum crystallizer without external classifying seed bed The flashing of solution keeps the crystals in suspension until they are large enough to fall into the discharge pipe from which they are removed as a slurry by the pump. The propellers keep the liquid thoroughly stirred and prevent the feed solution form reaching the discharge pioe without flashing.

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Application
Preformulation studies: Study of crystalline structure form the core of preformulation studies because molecules make crystals, crystals make particles, and particles make dosage forms. Novel research in crystallography of new entities involves studies of amorphous forms to learn how local properties contribute to the chemical reactivity of these short-interacting forms

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Application
Manifestation of gout: Gout usually manifests itself as a sudden excruciating pain in the big toe (usually of men), although other joints such as the ankle, heel, instep, knee, wrist, elbow, fingers or spine may be affected. It is due to the precipitation of needle-like crystals of uric acid, in the form of monosodium urate, on the articular cartilage of joints when the levels of uric acid in blood serum exceed a critical solubility level (approximately 6.7 mg/dL).

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Achyut Bikram Thapa a.abthapa@gmail.com

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