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Vol - I , ISSUE - IV May 2011 : Chemistry

Author : Mr. K.R.Shinde, Mr.S.D.Patil and A.S.Dhake

Article : Recrystallization

ABSTRACT :

Recrystallization is clears that the of the natural product or synthetic compound is most

important in the preparation of pure drug compound. It is method mostly applicable to the

solid compound. The choice of solvent required for the recrystallization is depend on the

solubility of pure and impure compound in given solvent. In this review given the various

process/steps involved in the recrystallization method. The purity of recrystallized materials

can be determined by X-ray analysis, NMR, IR,X-ray crystallography and other analytical

methods.

KEYWORDS :

Recrystallization, Filtration, organic Solvent, purification& drying agent.

INTRODUCTION :

Recrystallization is the primary method for purifying solid organic compounds.

Compounds obtained from natural sources or from reaction mixtures almost always contain

impurities. The impurities may include some combination of insoluble, soluble, and colored

impurities. To obtain a pure compound these impurities must be removed. Each is removed

in a separate step in the recrystallization procedure. To understand the recrystallization

process, solubility behavior must first be considered. It is often stated that "like dissolves

like". More correctly, it should be stated that "compounds having similar structural features

will be soluble in one another". Some obvious structural features that may affect solubility

include polarity and the ability to hydrogen bond. For example, a compound having just a

few carbons and an alcohol functional group (FG) would be expected to be soluble in

solvents that have a few carbons and an alcohol FG or in some other polar solvent, and to

be less soluble in nonpolar solvents. Conversely an alkenes would be expected to show the

opposite solubility behavior. In most cases though it is not as simple as this. If for example

a compound has lots of carbons and hydrogens (> 6 C's) and just one alcohol group, the

solubility will be dominated more by the alkyl part of the molecule than by the alcohol part,

and the compound will show a solubility behavior more like that of an alkanes. For known

compounds it is useful to consider the structure of the compound when choosing a

recrystallization solvent. An educated guess can save some time. Usually however, the

structure of a compound may not be known so the solvent must be chosen by carrying out

solubility tests. The first part of this experiment involves carrying out solubility tests on

known compounds. Later on such solubility tests will be used to find a suitable

recrystallization solvent for an unknown compound. A compound usually exhibits one of

three general solubility beha-viors: (1), the compound has a high solubility in both hot and

cold solvent, (2), the compound has a low solubility in both hot and cold solvent, and (3),

the compound has a high solubility in hot solvent and a low solubility in cold solvent.

Solvents which exhibit the first two behaviors are not useful for recrystallizing a

compound. A solvent showing the third behavior, that is, high solubility at high

temperatures and low solubility at low temperatures, is one that is suitable for use as a

recrystallization solvent. Consider the three different types of impurities that may be

present in a sample: soluble, insoluble, and colored. In theory, insoluble impurities can be

removed from a compound fairly easily. The compound is dissolved in a solvent, the

solution is filtered to remove the insoluble impurities, and the solvent evaporated to

produce the solid compound. The insoluble impurities are left behind in the filter paper.

Colored impurities can be removed in a similar way but with an additional step. The solid is

dissolved in a solvent, activated charcoal is added, the solution is filtered as before, and the

solvent is evaporated to produce the solid compound. The charcoal, which has adsorbed the

colored impurities, is left behind in the filter paper. The third type of impurity, the soluble

impurity, cannot be filtered out because it has solubility characteristics similar to those of

the desired compound (hence the name soluble impurity). To remove soluble impurities,

first, by doing solubility tests, a suitable solvent is chosen (high solubility in hot solvent,

low solubility in cold solvent). The soluble impurities are then removed as follows: the

desired compounds along with the soluble impurities are dissolved in a minimum of near-

boiling solvent. The solution is then allowed to cool slowly and without interruption. As the

solution cools, the solubility of the compound (and of the soluble impurities) decreases, the

solution becomes saturated with the desired compound, and the compound begins to

crystallize. Because formation of crystals is a highly selective process that usually excludes

foreign molecules, only crystals of the desired compound form. Because the soluble

impurities are present in smaller amounts, the solution never becomes saturated with the

impurities, so the impurities remain in solution even after the solution has cooled

Removing the solution from the crystals thus removes the solvent and the soluble

impurities from the desired crystals. A final rinse with a minimum of ice-cold solvent

followed by its removal cleans off any residual soluble impurities clinging to the surface of

the desired crystals. After allowing the sol-vent to evaporate, pure crystals of desired

compound should remain. The weight and usually the MP of the crystals would be

determined, and along with the % recovery, would be included in the report In practice, by

following a set procedure, the same solvent is used throughout the whole recrystallization

process, and the impurities are removed one by one. Note that in any recrystallization some

of the desired product is sacrificed and the recovery will be less than 100%. This is because

even at the lower temperatures the desired compound has some finite solubility in the

recrystallization solvent and is thus lost when solvent and soluble impurities are removed.

Recrystallization :

It is method of purifying of organic compounds. The purification of impure crystalline

compound by crystallization from a suitable solvent or mixture of solvent is called as

recrystallization. The principle behind recrystallization is that the amount of solute that can

be dissolved by a solvent increases with temperature. In recrystallization, a solution is

created by dissolving a solute in a solvent at or near its boiling point. At this high

temperature, the solute has a greatly increased solubility in the solvent, so a much smaller

quantity of hot solvent is needed than when the solvent is at room temperature. When the

solution is later cooled, after filtering out insoluble impurities, the amount of solute that

remains dissolved drops precipitously. At the cooler temperature, the solution is saturated at

a much lower concentration of solute. The solute that can no longer be held in solution

forms purified crystals of solute, which can later be collected.

Recrystallization works only when the proper solvent is used. The solute must be

relatively insoluble in the solvent at room temperature but much more soluble in the solvent

at higher temperature. At the same time, impurities that are present must either be soluble

in the solvent at room temperature or insoluble in the solvent at a high temperature. For

example, if you wanted to purify a sample of Compound X which is contaminated by a

small amount of Compound Y, an appropriate solvent would be one in which all of

Compound Y dissolved at room temperature because the impurities will stay in solution

and pass through filter paper, leaving only pure crystals behind.

Insulin:

Insulin mostly obtained from animal origin, but this are could develop an allergy of

other types of reaction to the foreign protein. Insulin zinc suspension ( crystalline) :- Is a

sterile, buffered suspension of insulin in the form a complex obtained by the addition of

zinc chloride to insulin in a manner such that the insulin is in the form of crystal (show in

above fig) insoluble in water. The solution is partially neutralized to allow crystallization to

occur and the pH of the crystalline suspension is adjusted to about 7.2. [1, 2]

The most typical situation is that a desired "compound A" is contaminated by a small

amount of "impurity B". There are various methods of purification that may be attempted.

which includes recrystallization. There are also different recrystallization techniques that

can be used such as:

Single-solvent recrystallization

Typically, the mixture of "compound A" and "impurity B" are dissolved in the smallest

amount of solvent to fully dissolve the mixture, thus making a saturated solution. Normally

the solvent is warmed before use, increasing solubility. The solution is then allowed to

cool. As the solution cools the solubility of compounds in solution drops. This results in the

desired compound dropping (recrystallizing) from solution. The slower the rate of cooling,

the bigger the crystals formed.

Solvent added to compound Solvent heated to give saturated compound solution Saturated compound solution allowed to cool over time to give crystals and a saturated solution and follow the filtration process. [3]

The original Boost synthesis of Ibuprofen consists of six steps, started with the Friedel-

crafts acetylation of isobutylbenzen and it recrystallized by using a HCL (aq). The

crystallization process requires an initiation step. Once a small crystal has formed, more

crystals can grow from that crystal. Since "Compound A" is in excess this will usually

result in these crystals forming first and thus leaves a greater ratio of impurity in solution.

Thus the resulting solid is more pure than the original mixture. The level of purity can then

be checked by taking a melting point range of the solid and comparing it to an accepted

melting point range, if one exists. Compounds that are more pure have less melting point

depression and melt over a narrower temperature range. Naturally, other analytical

techniques can also be used to assess compound purity, including NMR spectroscopy and

elemental analysis. [4, 11]

This purification technique results in the inevitable loss of the part of "compound A"

that remains in solution. A yield of 80% would be considered quite good. However, the

impure solution can be concentrated and the procedure repeated to gather a "second crop"

of crystals. Successful recrystallization depends on finding the right solvent. This is usually

a combination of prediction/experience and trial/error. The mixture must be soluble at

higher temperatures, and must be insoluble (or have low solubility) at lower temperatures.

[14]

Multi-solvent recrystallization

This method is the same as the above but where two (or more) solvents are used. This

relies on both "compound A" and "impurity B" being soluble in a first solvent. A second

solvent is slowly added. Either "compound A" or "impurity B" will be insoluble in this

solvent and precipitate, whilst the other of "compound A"/"impurity B" will remain in

solution. Thus the proportion of first and second solvents is critical. Typically the second

solvent is added slowly until one of the compounds begins to crystallize from solution and

then the solution is cooled. Heating is not required for this technique but can be used.[10,1]

Solvent added to compound Solvent heated to give saturated compound solution Second solvent added to compound solution to give mixed solvent system Mixed solvent system allowed to cool over time to give crystals and a saturated mixed solvent

system and follow the filtration process.

The reverse of this method can be used where a mixture of solvent dissolves both A and

B. One of the solvents is then removed by distillation or by an applied vacuum. This results

in a change in the proportions of solvent causing either "compound A" or "impurity B" to

precipitate.

First solvent added to compound Solvent heated to give saturated compound solution Second solvent added to compound solution to give first mixed solvent system Volatile first solvent is removed from first mixed solvent system to give a second mixed solvent system Second mixed solvent system allowed to cool over time to give crystals and a saturated second mixed solvent system. [26, 25]

Table no 1:-The common solvents available for recrystallization are

collected in the Table [10]

SOLVENT B.P. REMARKS

Water (distilled) 100C To be used whenever suitable.

Diethyl ether 35C Inflammable; avoid wherever possible.

Acetone 56C Inflammable; should preferably be dried

before use.

Chloroform 61C Non-inflammable; vapor toxic.

Methyl alcohol 64.5C Inflammable; poisonous.

Carbon tetrachloride 77C Non-inflammable; vapor toxic

Ethyl acetate 78C Inflammable

Methylated (industrial) spirit 77-82C Inflammable

Rectified spirit (95% C2H5OH) 78C Inflammable

Ethyl alcohol (absolute) 78C Inflammable

Benzene 80C Inflammable

Light petroleum 40-60C Inflammable

Acetic acid (glacial) 118C Not very inflammable; pungent vapors.

Removal of Traces of Coloring Matter and Resinous Products: Use of Decolorizing Carbon

:

The crude product of an organic reaction may contain a colored impurity. Upon

recrystallization, this impurity dissolves in the boiling solvent and is partly adsorbed by the

crystals as they separate upon cooling; yielding a colored product .Sometimes the solution

is slightly turbid owing to the presence of a little resinous matter or a very fine suspension

of an insoluble impurity, which cannot always be removed by simple filtration. These

impurities can be removed by boiling the substance in solution with a little decolorizing

charcoal for 5-10 minutes, and then filtering the solution while hot as described. The

decolorizing charcoal adsorbs the colored impurity and holds back resinous, finely-divided

matter, and the filtrate is usually free from extraneous colour, and therefore deposits pure

crystals. An excessive quantity of decolorizing agent must be avoided, since it may also

adsorb some of the compound which is being purified. The exact quantity to be added will

depend upon the amount of impurities present; for most purposes 1-2 par cent by weight of

the crude solid will be found satisfactory .If this quantity is insufficient, the operation

should be repeated with a further 1-2 per cent of fresh decolorizing charcoal. The most

widely known form of decolorizing carbon is animal charcoal (also known as bone black or

bone charcoal); it is the least expensive, but by no means the best. [10, 1]

Hot filtration-recrystallization

Hot filtration can be used to separate "compound A" from both "impurity B" and some

"insoluble matter C". This technique normally uses a single-solvent system as described

above. When both "compound A" and "impurity B" are dissolved in the minimum amount

of hot solvent, the solution is filtered to remove "insoluble matter C". This matter may be

anything from a third impurity compound to fragments of broken glass. For a successful

procedure, one must ensure that the filtration apparatus is hot in order to stop the dissolved

compounds crystallizing from solution during filtration, thus forming crystals on the filter

paper or funnel.

One way to achieve this is to heat a conical flask containing a small amount of clean

solvent on a hot plate. A filter funnel is rested on the mouth, and hot solvent vapors keep

the stem warm. Jacketed filter funnels may also be used. The filter paper is preferably

fluted, rather than folded into a quarter; this allows quicker filtration, thus less opportunity

for the desired compound to cool and crystallize from the solution. [1,12]

Often it is simpler to do the filtration and recrystallization as two independent and

separate steps. That is dissolve "compound A" and "impurity B" in a suitable solvent at

room temperature, filter (to remove insoluble compound/glass), remove the solvent and

then recrystallize using any of the methods listed above. [14]

Filtration with Suction :

The use of suction renders rapid filtration possible and also results in a more complete

removal of the mother liquor than filtration under atmospheric pressure. A filter paper is

selected (and trimmed, if necessary) of such size that it covers the entire perforated plate,

but its diameter should be slightly less then the inside diameter of the funnel; the filter

paper should never be folded up against the sides of the funnel. The filter paper is

moistened with a few drops of the solvent used in the recrystallization (or with a few drops

of the clear supernatant liquid), and the suction of the pump is applied; the filter paper

should adhere firmly to, and completely cover, the perforated plate of the funnel and thus

prevent any solid matter from passing under the edge of the paper into the flask below. The

mixture of crystals and mother liquor is then immediately filtered through the funnel under

gentle suction. Gentle suction is often more effective in filtration than powerful suction,

since in the latter case the finer particles of the precipitate may reduce the rate of filtration

by being drawn into the pores of the filter paper. [1] If the solvent constituting the

crystallization medium has a comparatively high boiling point, it is advisable to wash the

solid with a solvent of low boiling point in order that the ultimate crystalline product may

be easily dried; it need hardly be added that the crystals should be insoluble or only very

sparingly soluble in the volatile solvent. The new solvent must be completely miscible with

the first, and should not be applied until the crystals have been washed at least once with

the original solvent. * Solvent added to a mixture of compound + insoluble substance Solvent heated to give saturated compound solution + insoluble substance Saturated compound solution filtered to remove insoluble substance Saturated compound solution allowed to cool over time to give crystals and a saturated solution

Mechanisms of recrystallization :

Recystallization manly going through the process of crystallization. Again and again

crystallization wills results into a pure compound so that the crystallization is an important

operation of the recrystallization method.

1) 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.

Crystallization is also a chemical solid-liquid separation technique, in which mass transfer

of a solute from the liquid solution to a pure solid crystalline phase occurs. Crystallization

phenomenon as per the steps involed ,

A= supersaturation.

B= nucleation.

C= crystal growth.

(A) Supersaturation:- The solution in which concentration of solute is greater than the

saturation concentration is known as supersaturation. [9]

When a solid is brought in contact with the solvent , the attractive forces of the liquid

tends to break apart the surface of the solid and disperse its ion or molecules in to the liquid

in the form of discrete mobile units, this process is known as solution. A saturated solution

is one in which the solid is in equilibrium with its solution at given temperature. It is a step

of thermodynamic equilibrium at a specifide temperature.

If we analyae the solution process on the basis of hole theory then a three step are

involved.

1) A solute is separated into its molecules or ions.

2) Formetion of hole or cavity in the solvent and,

3) Solute occupies hole in the solvent.

A Saturated solution is one ,where all cavities of the solvent are occupied by solute

molecules.If the solution which is saturated is cooled or evaporated slightly then some

solute molecule are thrown out of the solvent cavities as energy is reduced in the first and

solvent hole number reduction in the later case.The solution in which concentration of

solute is greater than the saturation concentration is known as supersaturation (S) may be

expressed as,

S = C/C*.

Where C = concentration of solution.

C*= Equilibrium saturation concentration at given temperature.

(B) Nucleation:- Nucleation is the step where the solute molecules dispersed in the

solvent start to gather into clusters, on the nanometer scale (elevating solute concentration

in a small region), that becomes stable under the current operating conditions. These stable

clusters constitute the nuclei. However when the clusters are not stable, they redissolve

Therefore; the clusters need to reach a critical size in order to become stable nuclei. Such

critical size is dictated by the operating conditions (temperature, supersaturation, etc.). It is

at the stage of nucleation that the atoms arrange in a defined and periodic manner that

defines the crystal structure note that "crystal structure" is a special term that refers to the relative arrangement of the atoms, not the macroscopic properties of the crystal (size

and shape), although those are a result of the internal crystal structure. [7]

Ones supersaturation is achived nucleation is a next essental step for crystallization to

occure.

1) Primary nucleation:-

This is the mode of nucleation which occurs mainly at high level of super saturation and

is most prevalent during unseeded crystallization. Nucleation can be either homogeneous,

without the influence of foreign particles, or heterogeneous, with the influence of foreign

particles. Generally, heterogeneous nucleation takes place more quickly since the foreign

particles act as a scaffold for the crystal to grow on, thus eliminating the necessity of

creating a new surface and the incipient surface energy requirements. [22]

Heterogeneous nucleation can take place by several methods. Some of the most typical

are small inclusions, or cuts, in the container the crystal is being grown on. This includes

scratches on the sides and bottom of glassware. A common practice in crystal growing is to

add a foreign substance, such as a string or a rock, to the solution, thereby providing a

nucleating site for the project and speeding up the time it will take to grow a crystal. [23]

(a) Homogeneous nucleation:- formation of stable crystal nuclei within a homogeneous

fluid is called homogeneous nucleation. During nucleation molecule / ions forming nucleus

should come together, for which they have to overcome the tendency of redissolve. They

also have to get orientated in a fixed lattice structure. Around 10-1000 such molecule are

necessary to form a stable nucleus. This cannot happen by simultaneous collision of

molecules which will be a rare chance to take place by a sequence of bimolecular addition

as,

A + A = A

A + A = A

A(n-1) + A = An (critical cluster)

Further addition of molecules to this critical cluster results in a nucleus. The rate of

nucleation is given by Arrhenius equation as follow,

J = Aexp (- G/KT)

Where J = rate of nucleation. A=Activation energy K= Boltzmann constant G = Overall

excess free energy between the solid particle of solute and solute in solution. T =

temperature in K. The homogeneous nucleation occurs in perfectly clean system without stirrer. The creation of a nucleus implies the formation of an interface at the boundaries of a

new phase. [7]

Liquids cooled below the maximum heterogeneous nucleation temperature (melting

temperature), but which are above the homogeneous nucleation temperature (pure

substance freezing temperature) are said to be supercooled. This is useful for making

amorphous solids and other metastable structures, but can delay the progress of industrial

chemical processes or produce undesirable effects in the context of casting. Supercooling

brings about supersaturation, the driving force for nucleation. Supersaturation occurs when

the pressure in the newly formed solid is less than the vapor pressure, and brings about a

change in free energy per unit volume, Gv, between the liquid and newly created solid

phase. This change in free energy is balanced by the energy gain of creating a new volume,

and the energy cost due to creation of a new interface. When the overall change in free

energy, G is negative, nucleation is favored. [17] Some energy is consumed to form an interface, based on the surface energy of each

phase. If a hypothetical nucleus is too small (known as an unstable nucleus or "embryo"),

the energy that would be released by forming its volume is not enough to create its surface,

and nucleation does not proceed. The critical nucleus size can be denoted by its radius, and

it is when r=r* (or r critical) that the nucleation proceeds. [5]

(b) Heterogeneous nucleation:- True homogeneous nucleation is a very difficult event

because the super cooled system unknowingly get seeded by the atmospheric dust which

contain active particles or heteronuclei in liquid solution lies in the range of 0.1-1um. The

overall free energy change associated with the formation of critical nucleus under

heterogeneous condition is less than the corresponding free energy change associated with

homogeneous condition. In the presence of heteronuclei, nucleation can be induced at

degrees of supercooling lower than those required for spontaneous nucleation.

Heterogeneous nucleation occurs much more often than homogeneous nucleation. It forms

at preferential sites such as phase boundaries or impurities like dust and requires less

energy than homogeneous nucleation. At such preferential sites, the effective surface

energy is lower, thus diminished the free energy barrier and facilitating nucleation. Surfaces

promote nucleation because of wetting contact angles greater than zero between phases encourage particles to nucleate. The free energy needed for heterogeneous nucleation is

equal to the product of homogeneous nucleation and a function of the contact angle In the

case of heterogeneous nucleation, some energy is released by the partial destruction of the

previous interface. For example, if a carbon dioxide bubble forms between water and the

inside surface of a bottle, the energy inherent in the water-bottle interface is released

wherever a layer of gas intervenes, and this energy goes toward the formation of bubble-

water and bubble-bottle interfaces. The same effect can cause precipitate particles to form

at the grain boundaries of a solid. This can interfere with precipitation strengthening, which

relies on homogeneous nucleation to produce a uniform distribution of precipitate particles.

[7,9]

Pure water freezes at 42C rather than at its freezing temperature of 0C if no crystal nuclei, such as dust particles, are present to form an ice nucleus.

Presence of cloud condensation nuclei is important in meteorology because they are often in short supply in the upper atmosphere .

All natural and artificial crystallization process (of formation of solid crystals from a homogeneous solution) starts with a nucleation event

Bubbles of carbon dioxide nucleate shortly after the pressure is released from a

container of carbonated liquid.

Nucleation in boiling can occur in the bulk liquid if the pressure is reduced so that the liquid becomes superheated with respect to the pressure-dependent boiling point. More

often nucleation occurs on the heating surface, at nucleation sites. Typically, nucleation

sites are tiny crevices where free gas-liquid surface is maintained or spots on the heating

surface with lower wetting properties. Substantial superheating of a liquid can be achieved

after the liquid is de-gassed and if the heating surfaces are clean, smooth and made of

materials well wetted by the liquid.

Nucleation is relevant in the process of crystallization of nanometer sized materials, and plays an important role in atmospheric processes.

Nucleation is a key concept in polymer, alloy and ceramic systems. In molecular biology, nucleation is used to term the critical stage in the assembly of a polymeric structure, such as a microfilament, at which a small cluster of monomers

aggregates in the correct arrangement to initiate rapid polymerization. For instance, two

actins molecules bind weakly, but addition of a third stabilizes the complex. This trimer

then adds additional molecules and forms a nucleation site. The nucleation site serves the

slow, or lag phase of the polymerization process.

Some champagne stirrers operate by providing many nucleation sites via high surface area and sharp corners, speeding the release of bubbles and removing carbonation from the

wine. [25,26]

At very low temperatures, rate of diffusion is low. As temperature increases, the rate of

diffusion increases; molecules are able to get to the site of nucleation at a fast enough rate

to promote growth of the nucleus. At temperatures significantly below melting temperature,

fluctuation of molecules is very low; the molecules are in a low energy state and do not

have enough energy to move around and nucleate. Nucleation rate is dominated by

diffusion. However, as temperature increases, molecular fluctuations increase and

molecules tend to escape from the nucleus, causing a decreased rate of nucleation. The time

required for steady state nucleation is known as the time-lag . (C) Crystal growth: - Crystal growth is a major stage of a crystallization process, which

typically follows an initial stage of either homogeneous or heterogeneous (surface

catalyzed) nucleation. It occurs from the addition of new atoms, ions, or polymer strings

into the characteristic arrangement of a crystalline Bravais lattice.

Quartz is one of the several thermodynamically stable crystalline forms of silica, SiO2

Crystal growth is the subsequent growth of the nuclei that succeed in achieving the

critical cluster size.

As soon as stable nuclei or the nuclei above the critical size are formed in a

supersaturated solution they begin to grow. During the growth of the crystal form solution.

Following steps are involved:-

1) Solute molecule breaks whatever bonds it has with the solvent.

2) These solute molecule migrate to the solid- liquid interface.

3) Adsorption and orientation of solute molecules in the crystal lattice.

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 (control of

crystal size and shape constitutes one of the main challenges in industrial manufacturing,

such as for pharmaceuticals). Crystalline solids are typically formed by cooling and

solidification from the molten (or liquid) state. According to the Ehrenfest classification of

first-order phase transitions, there is a discontinuous change in volume (and thus a

discontinuity in the slope or first derivative with respect to temperature, dV/dT) at the

melting point. Within this context, the crystal and melt are distinct phases with an

interfacial discontinuity having a surface of tension with a positive surface energy. Thus, a

metastable parent phase is always stable with respect to the nucleation of small embryos or

droplets from a daughter phase, provided it has a positive surface of tension. Such first-

order transitions must proceed by the advancement of an interfacial region whose structure

and properties vary discontinuously from the parent phase. [7]

Many compounds have the ability to crystallize with different crystal structures, a

phenomenon called polymorphism. Each polymorph is in fact a different thermodynamic

solid state and crystal polymorphs of the same compound exhibit different physical

properties, such as dissolution rate, shape (angles between facets and facet growth rates),

melting point, etc. For this reason, polymorphism is of major importance in industrial

manufacture of crystalline products.

a) Surface energy theory: - Gibbs and Curie postulated the surface energy theory for

crystal growth. It state that the crystal assumes that shape which has minimum surface

energy. It suggest that the crystal faces would grow at rate proportional to their respective

surface ener-gies. [9]

Artificial methods for crystallization :

For crystallization to occur from a solution it must be supersaturated. This means that

the solution has to contain more solute entities (molecules or ions) dissolved than it would

contain under the equilibrium (saturated solution). This can be achieved by various

methods, with 1) solution cooling, 2) addition of a second solvent to reduce the solubility of

the solute (technique known as antisolvent or drown-out), 3) chemical reaction and 4)

change in pH being the most common methods used in industrial practice. Other methods,

such as solvent evaporation, can also be used. The spherical crystallization has some

advantages.

Equipment for crystallization :

1. Tank crystallizers. Tank crystallization is an old method still used in some

specialized cases. Saturated solutions, in tank crystallization, are allowed to cool in open

tanks. After a period of time the mother liquid is drained and the crystals removed.

Nucleation and size of crystals are difficult to control. Typically, labor costs are very high.

[20]

2. Scraped surface crystallizers. One type of scraped surface crystallizer is the

Swenson-Walker crystallizer, which consists of an open trough 0.6 m wide with a

semicircular bottom having a cooling jacket outside. A slow-speed spiral agitator rotates

and suspends the growing crystals on turning. The blades pass close to the wall and break

off any deposits of crystals on the cooled wall. The product generally has a somewhat wide

crystal-size distribution. [22]

3. Double-pipe scraped surface crystallizer. Also called a rotator, this type of

crystallizer is used in crystallizing ice cream and plasticizing margarine. Cooling water

passes in the annular space. An internal agitator is fitted with spring-loaded scrapers that

wipe the wall and provide good heat-transfer coefficients.[23]

4. Circulating-liquid evaporator-crystallizer. Also called Oslo crystallizer. Here

supersaturation is reached by evaporation. The circulating liquid is drawn by the screw

pump down inside the tube side of the condensing stream heater. The heated liquid then

flows into the vapor space, where flash evaporation occurs, giving some

supersaturation.The vapor leaving is condensed. The supersaturated liquid flows down the

down flow tube and then up through the bed of fluidized and agitated crystals, which are

growing in size. The leaving saturated liquid then goes back as a recycle stream to the

heater, where it is joined by the entering fluid. The larger crystals settle out and slurry of

crystals and mother liquid is withdrawn as a product.

5. Circulating-magma vacuum crystallizer. The magma or suspension of crystals is

circulated out of the main body through a circulating pipe by a screw pump. The magma

flows though a heater, where its temperature is raised 2-6 K. The heated liquor then mixes

with body slurry and boiling occurs at the liquid surface. This causes supersaturation in the

swirling liquid near the surface, which deposits in the swirling suspended crystals until they

leave again via the circulating pipe. The vapors leave through the top. A steam-jet ejector

provides vacuum.

6. Continuous oscillatory baffled crystallizer (COBC). The COBC is a tubular baffled

crystallizer that offers plug flow under laminar flow conditions (low flow rates) with

superior heat transfer coefficient, allowing controlled cooling profiles, e.g. linear, parabolic,

discontinued, step-wise or any type, to be achieved. This gives much better control over

crystal size, morphology and consistent crystal products. [24]

Crystal production :

Macroscopic crystal production: for supply the demand of natural-like crystals with methods that "accelerate time-scale" for massive production and/or perfection.

o Ionic crystal production;

o Covalent crystal production.

Tiny size crystals: o Powder, sand and smaller sizes: using methods for powder and controlled

(nanotechnology fruits) forms.

Mass-production: on chemical industry, like salt-powder production.

Molecular structure and nuclear forces inside a typical molecule of a crystal. Many techniques, like X-ray crystallography and NMR spectroscopy, are widely used in

chemistry and biochemistry to Sample production: small production of tiny crystals for

material. Characterization controlled recrystallization is an important method to supply

unusual crystals, that are needed to reveal the determine the structures of an immense

variety of molecules, including inorganic compounds and bio-macromolecules.

o Thin film production.

Massive production examples:

"Powder salt for food" industry; Silicon crystal wafer production. Production of sucrose from sugar beet, where the sucrose is crystallized out from an aqueous solution.

Purification :

Used to improve and/or verify their purity.

Crystallization separates a product from a liquid feed stream, often in extremely pure

form, by cooling the feed stream or adding precipitants which lower the solubility of the

desired product so that it forms crystals.

Well formed crystals are expected to be pure because each molecule or ion must fit

perfectly into the lattice as it leaves the solution. Impurities would normally not fit as well

in the lattice, and thus remain in solution preferentially. Hence, molecular recognition is the

principle of purification in crystallization. However, there are instances when impurities

incorporate into the lattice, hence, decreasing the level of purity of the final crystal product.

Also, in some cases, the solvent may incorporate into the lattice forming a solvate. In

addition, the solvent may be 'trapped' (in liquid state) within the crystal formed, and this

phenomenon is known as inclusion.

Drying of Recrystallized Material

In order to dry the crystals, the Buchner funnel is inverted over two or three thicknesses

of drying paper (i.e., coarse-grained, smooth surfaced filter paper) resting upon a pad of newspaper, and the crystalline cake is removed with the aid of a clean spatula; several

sheets of drying paper are placed on top and the crystals are pressed firmly. It the sheets

become too soiled by the mother liquor absorbed, the crystals should be transferred to fresh

paper. The disadvantage of this method of rapid drying is that the recrystallized product is

liable to become contaminated with the filter paper fiber. Another method, which is

especially suitable for low melting point solids or solids which decompose at low

temperatures, is to place the material on a porous plate or pad of drying paper, and to cover the latter with another sheet of filter paper perforated with a number of holes or with

a large clock glass or sheet of glass supported upon corks. The air drying is continued until

the solvent has been completely eliminated. For solids which melt above 100 and are

stable at this temperature, drying may be carried out in a steam oven. The crystals from the

Buchner funnel should then be placed on a clock glass or in an open dish. The best method

of drying, if time permits, is to place the crystals in a desiccators containing an agent

appropriate substance (usually anhydrous calcium chloride, silica gel, or concentrated

sulphuric acid) to absorb the solvent. More efficient and more rapid drying is obtained with

the aid of vacuum desiccators before attempting a melting point determination as a check

on the purity; care must be taken to ensure a perfectly dry sample of the compound since

traces of solvent may lower the melting point appreciably. [1, 10]

Drying of Liquids or Solutions of Organic Compounds in Organic Sol-vents :

Liquids or solutions of organic substances in organic solvents are usually dried by

direct contact with a solid inorganic drying agent. The selection of the desiccant will be

governed by the following considerations:-(i) it must not combine chemically with the

organic compound;(ii) it should have a rapid and effective drying capacity; (iii) it should

not dissolve appreciably in the liquid; (iv) it should be as economical as possible; and (v) it

should have no catalytic effect in promoting chemical reactions of the organic compound,

such as polymerization, condensation reactions, and auto-oxidation. It is generally best to

shake the liquid with small amounts of the drying agent until no further action appears to

take place: too large an excess is to be avoided in order to keep absorption losses down to a

minimum. If sufficient water is present to cause the separation of a small aqueous phase

(e.g., with calcium chloride), this must be removed and the liquid treated with a fresh

portion of the desiccant. [8]

Drying of Solid Organic Compounds :

A solid, moist with water or a volatile organic solvent, may be dried in the open air by

spreading it in this layer on several layers of absorbent filter paper; the whole should be

covered by a sheet of glass, clock glass or absorbent paper resting upon corks in order to

protect it from dust. This method is rather time-consuming if water is to be completely

removed. More effecting drying may be secured by placing the substance in thin layers

upon clock glasses in steam oven or in a thermostatically-controlled, electrically heated

oven; the temperature of the drying oven must be below the melting or decomposition point

of the compound and it is recommended that a preliminary test be made with a small

sample.[10]

A list of the common dying agent as follows :

Anhydrous calcium chloride = This reagent is widely employed because of its high

drying capacity and its cheapness. It has a large water-absorption capacity (since it forms

CaCl2, 6H2O below 30.) but is not very rapid in its action; sample time must therefore be

given for desicca-tion.

Anhydrous magnesium sulphate. = This is an excellent, neutral desiccating agent and is

in-expensive. It is rapid in its action chemically inert and fairly efficient, and can be

employed for most compounds including those (esters, aldehydes, ketones, nitriles, amides,

etc.) to which calcium chloride is not applicable.

Aluminium oxide = The commercial material, activated alumina, is made from aluminium hy-droxide; it will absorb 15-20 par cent of its weight of water, can be re-

activated by heating at 175 for about seven hours, and does not appreciably deteriorate with

repeated use. Its main application is as a drying agent for desiccators.

Boric anhydride = This is a powerful and efficient desiccant and will absorb up to about

25 par cent of its weight of water. It is useful for drying formic acid.

Phosphorus pentoxide = This is an extremely efficient reagent and is initially rapid in

its reaction. Phosphoric oxide is difficult to handle, channels badly, is expensive, and tends

to from a syrupy coating on its surface after a little use. A preliminary drying with

anhydrous magnesium sulphate, etc., should precede its use. Phosphorus pentoxide is only

employed when extreme desiccation is required. It may be used for hydrocarbons, ethers,

alkyl and aryl halides, and nitriles, but not for alcohols, acids, amines and ketones. [10]

Table no 2:- Common Drying Agents for Organic Compounds

Alcohols Anhydrous potassium carbonate; anhydrous magnesium or

calcium sulphate; quicklime.

Alkyl halides

Aryl halides

Anhydrous calcium chloride; anhydrous sodium, magnesium or

calcium sulphate; phosphorus pentoxide.

Saturated and

aromatic

hydrocarbons

Ethers

Anhydrous calcium chloride; anhydrous calcium sulphate;

metallic sodium; phosphorus pentoxide.

Aldehydes Anhydrous sodium, magnesium or calcium sulphate.

Ketones Anhydrous sodium, magnesium or calcium sulphate; anhydrous

potassium carbonate.

Organic bases

(amines)

Solid potassium or sodium hydroxide; quicklime; barium oxide

Organic acids Anhydrous sodium, magnesium or calcium sulphate.

Laboratory Tutorials - Recrystallization : Background

The principle behind recrystallization is that the amount of solute that can be dissolved

by a solvent increases with temperature. In recrystallization, a solution is created by

dissolving a solute in a solvent at or near its boiling point. At this high temperature, the

solute has a greatly increased solubility in the solvent, so a much smaller quantity of hot

solvent is needed than when the solvent is at room temperature. When the solution is later

cooled, after filtering out insoluble impurities, the amount of solute that remains dissolved

drops precipitously. At the cooler tem-perature, the solution is saturated at a much lower

concentration of solute. The solute that can no longer be held in solution forms purified

crystals of solute, which can later be collected.

Recrystallization works only when the proper solvent is used. The solute must be

relatively insoluble in the solvent at room temperature but much more soluble in the solvent

at higher temperature. At the same time, impurities that are present must either be soluble

in the solvent at room temperature or insoluble in the solvent at a high temperature. For

example, if you wanted to purify a sample of Compound X which is contaminated by a

small amount of Compound Y, an appropriate solvent would be one in which all of

Compound Y dissolved at room temperature because the impurities will stay in solution

and pass through filter paper, leaving only pure crys-tals behind. Also appropriate would be

a solvent in which the impurities are insoluble at a high temperature because they will

remain solid in the boiling solvent and can then be filtered out. When dealing with

unknowns, you will need to test which solvent will work best for you. Ac-cording to the

adage "Like dissolves like," a solvent that has a similar polarity to the solute being

dissolved will usually dissolve the substance very well. In general, a very polar solute will

easily be dissolved in a polar solvent and will be fairly insoluble in a non-polar solvent.

Frequently, having a solvent with slightly different polarity characteristics than the solute is

best because if the polarity of the two is too closely matched, the solute will likely be at

least partially dissolved at room temperature. [22]

Procedure

There are five major steps in the recrystallization process: dissolving the solute in the

sol-vent, performing a gravity filtration, if necessary, obtaining crystals of the solute,

collecting the solute crystals by vacuum filtration, and, finally, drying the resulting crystals.

Dissolving the solute in the solvent

Add a small portion of boiling solvent to the beaker that contains the impure sample

and a boiling chip.

Heat the beaker containing the solute and continue adding boiling solvent

incrementally until all of the solute has been dissolved. If additional solvent can be added

with no appreciable change in the amount of solute present, the particulate matter is

probably insoluble impurities.[12]

Hot Gravity Filtration

This step is optional if there is no visible particulate matter and the solution is the

expected color (most organic compounds are white or light yellow)

If the solution is not the expected color, remove the boiling solution from the heat and

al-low it to cool to beneath the boiling point of the solvent. Add a small amount of

activated carbon (about the size of a pea) and mix the solution. If too much activated

carbon is used, excessive loss of the desired product will result. Boil the solution containing

the activated carbon for 5 to 10 minutes. A filter aid will need to be placed in the filter

paper to remove the carbon in the following steps.

Flute a piece of filter paper and place it inside of a stem less funnel. A funnel with a

stem is prone to premature recrystallization inside the stem because the filtrate can cool as

it passes through the stem. At these cooler temperatures, crystals are likely to form.

Heat a beaker that contains some of your recrystallization solvent. Place the funnel and

filter paper assembly in the beaker so that the rising vapors from the boiling solvent can

heat the funnel and filter paper. Having the set up heated before filtration will prevent

crystals from form-ing on the paper and in the funnel (see Figure 2 below).[24]

Hot gravity filtration. Keeping the set up hot prevents crystals from

forming prematurely.

Keeping the solution very hot so the solute stays dissolved, pour the solution through

the funnel and filter paper assembly. As the filtrate begins to accumulate, heat the

receptacle beaker; the resulting vapors will help to prevent any crystallization in the funnel

or on the filter paper.

If the funnel was properly heated before filtration, all of the solution will have passed

through and no crystals will have formed on the paper or in the funnel. If crystals have

formed, pouring a small amount of boiling solvent through the funnel will dissolve these. If

the solution is still discolored after using activated carbon and filtering, either the color is

from the compound and will not go away or you need to repeat the step with the addition of

activated carbon.

The solution should be allowed to cool slowly to room temperature. Gradual cooling is

conducive to the formation of large, well-defined crystals.

Vacuum Filtration

Agitate the crystals with a fire polished glass-stirring rod before pouring the mother-

liquor along with the crystals through the Buchner funnel. Apply the maximum amount of

suction pos-sible using the aspirator.

Some crystals may have been left behind in the beaker; there are two ways to effect a

quantitative transfer of all of this material. Either use a portion of the filtrate to rinse the

beaker or use a rubber policeman on the end of your stirring rod to scrape the remaining

crystals into the Buchner funnel.

When the crystals have been collected and washed, allow the aspirator to run for

several minutes so that the crystals have an opportunity to dry.

Drying the Crystals :

When the crystals have been dried as much as possible in the Buchner funnel, use a

spatula to remove them to a beaker or crystallizing dish. This will ensure that the crystals

are not con-taminated by filter paper fibers as they dry.

After removing all the crystals from the filter paper, remove the filter paper and scrape

any remaining crystals from the funnel.

Spreading the crystals out in a beaker or a crystallizing dish will provide for the most

effi-cient drying as the crystals will have a maximum of exposed surface area.

When the crystals are dried, the purity of the sample can be measured by performing

melting point determination.

What to do if crystals don't form; crystals don't form upon slow cooling of the solution

to room temperature there are a variety of procedures you can perform to stimulate their

growth. First, the solution should be cooled in an ice bath. Slow cooling of the solut ion

leads to slow formation of crystals and the slower crystals form, the more pure they are.

Rate of crystallization slows as temperature decreases so cooling with an ice bath should

only be used until crystals begin to form; after they do, the solution should be allowed to

warm to room temperature so crystal formation occurs more slowly. If no crystals form

even after the solution has been cooled in an ice bath, take a fire polished stirring rod and

etch (scratch) the glass of your beaker. The small pieces of glass that are etched off of the

beaker serve as nuclei for crystal formation. If crystals still do not form, take a small

amount of your solution and spread it on a watch glass. After the solvent evaporates, the

crystals that are left behind can serve as seeds for further crystallization. Both these

methods of nucleation (i.e. etching and seed crystals) cause very rapid crystallization,

which can lead to the formation of impure crystals.[16]

Crystals will not form if there is a large excess of solvent. If no crystals form with the

methods already discussed, a portion of the solvent may need to be removed. This can be

accom-plished by heating the solution for a period of time in order to evaporate some

solvent. The new, concentrated solution, should be cooled, and the previously mentioned

methods to stimulate crystallization should again be attempted.

Another potential problem in recrystallization is that the solute sometimes comes out of

solution in the form of impure oil instead of forming purified crystals. This usually happens

when the boiling point of the solvent is higher than the melting point of the compound, but

this is not the only scenario in which this problem presents itself. If this begins to happen,

cooling the solution will not stimulate crystallization, it will make the problem worse. If an

oil begins to form, heat the solution until the oil portion dissolves and let the whole solution

cool. As the oil begins to form again, stir the solution vigorously to break up the oil. The

tiny beads of oil that result from this shaking may act as the nuclei for new crystal

formation.

APPLICATION OF RECRYSTALLIZATION :

Recrytallization is the purification method and it mostly applicable in organic chemistry

as well as in medicinal chemistry.Most of the medicinal compound can be purify by this

method,some example are given as follow ;

1) Acetanilide from water:- Weigh out 4gm of commercial acetanilide into a 250 ml

beaker. Add 80 ml of water and heat nearly to the boiling point. The acetanilide will appear

to melt and form an oil in the solu-tion. Add small portion of hot water ,whist stirring the

mixture and boiling gently until all the solid has dissolved (If solution is not colorless allow

to cool slightly ,add about 0.5gm of decol-orizing carbon ,and continue the boiling for a

few minutes in order to remove the colored impuri-ty.) Filter the boiling solution through a

fluted filter paper supported in a short necked funnel; if the solution can not be filtered in a

single operation keep the unfiltered portion hot by heating with a small flame over a wire

gauze .and filter it. Collect the filtrate in 250 ml beaker. When all the solution has been

filtered, partially cover the beaker containing the hot filtrate with a clock glass and cool

rapidly with stirring. Allow to stand for about 30 minute to complete the separa-tion of the

solid. Filter with the suction through a small Buchner funnel. Wash the crystal twice with

5ml portion of cold water. Allow to dry the crystal in air. Weigh the yield of recrystallized

material and determine the melting point. If the recrystallized product is not sufficiently

pure, repeat the recrystallization .Pure acetanilide have m. p 114c. [10]

2) Aspirin from ethanol:- The crude acetylsalicylic acid by dissolving it in 15ml hot

ethanol and pouring the solution into about 40ml of warm water. If a solid separated at this

point, warm the mixture until solution competes and allow the clear solution to cool slowly.

Beautiful needle-like crystal separate. Mp of aspirin =159c

3) Sulphanilic acid from water:- Uses 5.0gm of crude sulphanilic acid add 80ml of

water. Heat it up to boiling point range. Add 1gm of decolorizing carbon to the solution at

70-80 and continue the boiling for several minute. If the filtered solution is not colorless, it

must be boiled with a further 1gm of decoloriz-ing carbon. Filter the cold solution at pump.

Wash the crystal with a little cold water, dry and weigh the yield of recrystallized product

also melting point.

4) p-nitro acetanilide:- Transfer the crude product in the 100ml round-bottomed flask

fitted with reflux condenser, add 40-50ml of methylated spirit and heat on a water bath until

all the crystalline solid dissolves. Filter at the pump wash with a little cold alcohol and dry

in the air upon the filter paper. (The yellow 0-nitroacetanilide remain in the filtrate.) The

yield of p- nitroacetanilide a colorless crystalline solid of m. p 214c. [15]

5) Phenylazo-2-napthanol from glacial acetic acid:- Dissolve 5gm in 30-35ml glacial

acetic acid. Filter the recrystallized product with suction, wash with a little alcohol or

methylated spirit to eliminate acetic acid and dry upon filter paper. The yield of deep red

crystal is good. Pure phenylazo-2-napthanol has m. p. 131c. If m. p. is low recrystallized

and dry the product from alcohol.

Conclusion :

The review on the recrystallization is clears that the purification of the natural product

or synthetic compound is most important in the preparation of pure drug compound. It is

method mostly applicable to the solid compound. The choice of solvent required for the

recrystallization is depend on the solubility of pure and impure compound in given solvent.

The solvent use for recrystallization may be more than one. The compound can be boil and

filtration carry out either by gravity or using by the suction. (Under pressure.) The filter

material will be drying by using various drying agent. Finally the melting point of

recrystallized material can be taking. According to melting point the purity of compound

will be determine.

The purity of pharmaceutical drug compound is most important parameter in the study

of bioavailability of dosage form. The various mechanisms are incorporate in

recrystallization as crystal growth, nucleation, supersaturation.On the basis of purity one

can predict concentration of drug in the dosage required to produce therapeutic effect. The

large numbers of drug com-pound can be purifying by using this method. Drug may be

show the toxic effect if it is impure. The purity of recrystallized materials can be

determined by X-ray analysis, NMR, IR,X-ray crystallography and other analytical

methods.

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