Significance of recrystallization on pharmaceutical dosage form processing

Dr.A.V.Yadav

Recently in the field of pharmaceutical technology, great efforts are being directed towards the prefabrication of existing drug molecules in the way of solving problems related to poor water solubility, Dissolution, bioavailability, Flowability, compressibility, dosing problem, stability and toxicity.

Crystals can be modified by recrystallizing the drug in different ways, which affect the physical and physicochemical properties such as melting point, solubility, true density, dissolution profile, flowability and Tabletability.Recrystallization method is simple and inexpensive enough for scaling up to a commercial level. It reduces time and cost by enabling faster operation, less machinery and fewer personnel. It gives important advances in the different pharmaceutical dosage form technology.

Introduction:

Recently in the field of pharmaceutical technology, great efforts are being directed towards the prefabrication of existing drug molecules in the way of solving problems related to poor water solubility, bioavailability, Flowability, compressibility, dosing problem, stability and toxicity. ¹

Galenical methods ² are more convenient to solve bioavailability problems. For example, the free energy of the system can be increased by the use of polymorphic crystals or amorphous forms as realized in solid dispersions. ^3,4 however, manufacturing difficulties, problem in scaling up and stability problem limit their commercial use. Solubility and dissolution rate can also be optimized by special recrystallization techniques. ^5,6 Many drug substances form different crystal forms and crystal lattice with different polymorphic forms and internal packing arrangements. However, there are some drugs also exist whose crystals only have differences in their outer appearance these drugs form different habits without differences in the crystal lattice. Crystals can be modified by recrystallizing the drug in different ways, which affect the physical and physicochemical properties such as melting point, solubility, true density, dissolution profile, flowability and Tabletability. ^{7, 8,9}

N. Rasenack et.al. Prepared different crystal forms of the analgesic drug Ibuprofen by using the different crystallization condition viz-solvent change method, the temperature change method and the solvent evaporation method. Crystals were grown from different solvents. Different crystal forms with different properties were observed; cubic, needle shaped, and plate shaped crystal was obtained. Spherical agglomeration occurred when crystallization was carried out in acetonitrile or methanol. Flowability of these spherical crystals was increased. All crystals were determined as isomorphic by differential scanning calorimetry and X-ray analysis. ¹⁰ Recrystallizing method of different drugs shows he following significances on the pharmaceutical processing

• Impact of crystal habit on pharmaceutical processing:

Crystal habit of a drug is an important variable in pharmaceutical manufacturing. A number of basic physical properties such as solubility ¹¹ , dissolution rate, melting behavior, and certain micromeritic properties or performance characteristics, e.g. tablet compressibility ¹² , mechanical strength ¹³ , powder flow depend on the habit modification of a particular drug ¹⁴ . Furthermore these variations can alter the bioavailability and therapeutic response. Although isotropic crystals (cubic, spherical,) are the preferred habit modifications, the majority of drugs exist as non-isotropic crystals. Therefore, manipulative procedures to change to a move favorable crystal form are quite often called for. ^15,16

Changes in crystal habit accompanied with or without polymorphic transformation during processing storage can lead to serious implications of physical stability in dosage forms. Therefore to minimize variations in raw material characteristics, to ensure reproducibility of results during preformulation, and to correctly judge the cause of instability and poor performance of a dosage form, it is essential to recognize the importance of changes in crystal surface appearance and habit of pharmaceutical powders by recrystallization method. ^17,18

A Watanabe et al prepared Aspirin crystals having different types of habit by recrystalization of commercial products from various solvents. The dissolution behavior of these crystals was studied in an artificial gastric juice, and the dissolution constants were calculated by means of the Noyes-whitey equation using the specific surface area obtained from the habit parameters. It was found that the dissolution constants of crystals with different habits were not constant, and it seems that the values depend upon the ratio of the area (001) of to the sum of the areas of the remaining faces. it was also found that aspirin dissolved more easily when it was powdered than would be expected from the increased surface area. This phenomenon might be a result of the distortion of crystals. ¹⁹

• Compaction properties:

The majority of drugs used in tablets are produced by recrystallization from different solvents. It has been demonstrated that the use of alternative crystallization solvents can produced crystal with altered properties especially crystal habit, size, shape and compressibility. The nature and extents of these changes were depends on the recrystallization condition including the presence of impurities, types of solvents and the cooling rates. Pharmaceutical example of solvent induced crystal habit modification or change the morphology and workability of the drug using recrystalllization method includes   Nitrofurantion ²⁰ , Ibuprofen ²¹ and Hexamethylmelamine ²² , which show improvements in compaction behavior. The crystal habit of drug is an important variable in pharmaceutical manufacturing. Different crystal habit of particular drug posses different planes and thus differed not only in their specific surface but also in their free surface energy therefore they exhibit different physicochemical properties. The compaction properties of recrystallized crystal were evaluated by using fully instrumented single punch tablet machine. Compaction data were analyzed by the Heckel equation both during compaction and after ejection. 

• Polymer mediated crystals habit modification:

The control of crystallization process is often crucial in the production as well as processing of pharmaceutical drug materials. The recrystallizatioin process as well as the nature of recrystallization product is determined by the way that they are produced i.e. prehistory of the material. The control of particle size shape is essential for the control of downstream process such as dissolution compaction and milling. This may be achieved by variation of operational conditions such as degree of super saturation, temperature, pH and impurity. Inhibition of crystallization process during recrystallization process has been effectively used in different dosage form drug delivery. The degree of super saturation in these systems is high and they tend to crystallize by spontaneous nucleation. The added polymers act as anti-nucleating agents inhibiting nucleation as weld as growth 

Some of the polymers, which have been found to inhibit crystallization which are methylcellulose, Hyroxypropyl methyl celluose (HPMC), Polyvinyl pyrrolidone (PVP). These antinuclating polymers show reduction in crystallization and increase amorphous behavior gives better solubility and dissolution rate. The antinucleant polymer molecules are incompatible in both size and size of the host molecules of the growing crystals surface. Therefore their incorporation into the lattice alters growth characteristics of the host molecules ²³ .

• Solubility:

The insufficient solubility of many clinically established drug substances in water as well as in the aqueous gastric fluids cause problem in bioavailability. Enhancement of solubility and dissolution rate and oral bioavailability of poorly water-soluble drugs still one of the challenging aspects for the pharmaceutical technologists. ²⁴

The bioavailability of poorly water-soluble drug substances is a well-known difficulty to be coped with during the development of new drug substances. For Class II and IV – drugs according to the biopharmaceutics classification system ²⁵ , the dissolution rate is the limiting factor for the drug absorption rate. An enhancement in dissolution rate is important to attain suitable blood-levels of these drugs. ²

Solubility can also be increased by forming a complex with cyclodextrin. However, cyclodextrin preparation have several disadvantages, as the drug load is low and this method only works with drugs which fit into the cavity of the cyclodextrin and which have a high complex – forming constant. The molecular structure polarity, size and possibility for interactions with the cyclodextrin molecule are important factors determining the success of cyclodextrin preparation. ^26,2

• Dissolution rate:

The most unsolved problems concerning the dissolution properties of the drug, which arises during the preparation storage of the solid dosage form because of their crystallographic changes. The change includes polymorphic trasition, change in surface characteristics and the habit modification. Different crystal habit shows different dissolution rate and biological activity. Habit modification normally arises when the environments of growing crystals affects its external shape without changing its internal structure. This modification includes variation in size, relative developments of certain faces, kind and number of faces. Using the single crystal dissolution method Burt and Nickel (1979) demonstrate dissolution anisotropy in nickel sulphate a -hexahydrate crystals and predict that where different faces of the same crystals dissolve at different rate therefore the modification of crystal habit should affect the bulk dissolution rate. Nogami and Kato studied the absorption and excretion behavior of various commercial products of aspirin as well as various recrystallizaed crystal obtained from these product. It was found that the recrystallized thin crystal showed better dissolution and excretion behavior then commercial product. Therefore changing crystal habit by recrystallization gives significant effect on dissolution rate ^27,28 . 

N. Bolourtchian et. al studied physical characteristics of carbamazepine crystal grown from pure ethanol or acetone under different conditions by SEM  X-RD  and FT-IR, and for thermodynamic properties by DSC. Also the dissolution behavior and compaction properties of crystals were studied. Crystallization of carbamazepine by different methods specially watering out technique improved its dissolution rate and compactibility, produced high crushing strength compacts without capping.

• Polymorphism:  

The investigation of drug polymorphism is an important step in any reformulation study because polymorphism may have a considerable influence on solid-state properties that may be modifies biopharmaceutical and technological behavior of drug ²⁹ . Polymorphs are different crystalline forms of a drug that may have different physicochemical properties and biological activities. The existence of different crystal forms impact on key properties such as shelf life, vapiour pressure, solubility, bioavaialbility, morphology and density. It is vital to select the polymorph with the preferred properties and predict problems such as the unwanted crystallization of other polymorphs ³⁰ . The polymorphs differed from each other with respect to melting points, hardness, compression, solubility, bioavaliability, morphology and density. They can be prepared by recrystallizing the drug from different solvents under the divorce condition. The existence of the polymers can be determined by using techniques such as optical crystallography, X-ray powder diffraction and differential scanning calorimetry. Therefore the preparation of drug polymorphs by recrystallization techniques has emerged as on of the area of active research currently of interest in pharmaceutical field so as to improve the formulation related problems of drug molecules.  

A. David et al described the examination of the polymorphism of tumor inhibitory vincristine sulphate with a bisindole skeleton. The change in morality with temperature followed thermo-osmometrically. It could be shown by X-ray diffraction that a sample separated by cooling the solution had an amorphous structure and the proportion of the X-ray amorphous part of the substance along with the crystalline phase increased when the temperature of the solution was lowered from 50°C to 40°C to 30°C. At lower temperature, a mixture of molecular association of different coexists in dynamic equilibrium. Polymorphic modification of various compositions, characterized by different ratios of the crystalline and amorphous phase in the solid substance, can be obtained during the course of crystallization. ³¹

Metastable polymorphs: These are the polymorphs, which represents the higher energy state, lower melting point and higher aqueous solubility. Metastable polymorphs have greater aqueous solubility, dissolution rate and shows better bioavaliability.

Ex: Metastable polymorphs of Etoposide ³² , an anticancer drug was prepared by recrystallizing with different organic solvents. The raw Etopside crystalline powder has low oral bioavaliability because of low aqueous solubility, slow dissolution rate and instability in acidic pH. The metastable polymorphs of Etoposides was identified when it was recrystallized from isopropanol which gives two times in equilibrium solubility intrinsic dissolution rate as compared tom the raw Etoposide crystalline powder at 25 ⁰ C.

Figure 1.  The outline of differentiate habits and crystalline modification or polymorphs of solids. ^33,34

• Micro crystals formation:     

Microcrystallization is one of the common method for increasing the solubility and dissolution rate by forming high specific surface area. By using this technique small crystalline particles were obtained by disrupting of large crystals. Micronization by other methods shows several disadvantages over microcrystallization.

• Micronization by jar mills and fluid energy mills required high energy and manpower. 
• Disordered structure due to micronization influence the preformulation behavior.
• Surface energy changes due to micronization can influence on processing properties like flowability.
• Because of high surface area micronized particles often agglomerated and sticks to surfaces during processing
• Micronized particles have broad size distribution

Therefore preparation of microcrystals by recrystallization method to reduce the size of the poorly soluble drug particles. Recrystaliization was carried out by using solvent change or precipitation method by instantaneously mixing two liquids in presence of stabilizing agents. Thus by precipitating microcrystals in presence of stabilizing protective polymers a large and hydrophilized surface can be formed in a one process step without using any milling technique. The microcrystale are suitable drug formulation for drug dissolution enhancement. The manufacturing of microcrystals required common equipment and is able to perform in a single process step. They can be used in solid as well as liquid forms. ³⁵

• Lyotropic liquid crystals formation:

Lyotropic liquid crystals transitions occur with influence of solvents or recrystallization method. Lyotropic liquid crystals occur as a result of solvent induced aggregation of the constituent mesogens into micellar structure. Lyotropic liquid crystals or mesogens are typically amphiphilic, meaning that they are composed of both lyophilic (solvent attracting) and lyophobic (solvent repelling) part. This causes them to form into micellar structure in presence of solvent since the lyophobic end will stay together as the lyophilic ends extended outwards towards the solution. As the concentration of the solution increased and the solution is cooled, the micelles increase in size and eventually coalesce. This separates the newly formed liquid crystalline state from the solvent. This types of liquid crystalline states were mostly used for designing the sustain release drug delivery system. It is also used for improving the solubility and stability of insoluble drugs by incorporating it into micellar structure of liquid crystals. ³⁶          

• Spherical crystallization:

In 1986, Kawashima, Y., et al used the spherical crystallization technique for size enlargement of the drug in the field of pharmacy. Spherical crystallization was defined by Kawashima as “An agglomeration process that transforms crystals directly into compact spherical forms during the recrystallization process.” It also enables co-precipitation of drug and encapsulating polymer in the form of spherical particle. ³⁷ this technique involved selective formation of agglomerates of crystals held together by liquid bridges.

Advantages of Spherical Crystallization

• Spherical crystallization technique has been successfully utilized for improvement of flowability and compressibility of crystalline drug.
• This technique could enable subsequent processes such as separation, filtration, drying etc to be carried out more efficiently.
• By using this technology, physicochemical properties of pharmaceutical crystals are dramatically improved for pharmaceutical process i.e. milling, mixing and tabletting because of their excellent flowability and packability. ³⁸
• This technique may enable crystalline form of a drug to be converted into different polymorphic form and thus attain better bioavailability.
• For masking of the bitter taste of drug.
• Preparation of microsponges, microspheres and nanaospheres, microbaloons, nanoparticles and micro pellets as novel particulate drug delivery system.

The process is simple and inexpensive enough for scaling up to a commercial level. It reduces time and cost by enabling faster operation, less machinery and fewer personnel. It gives important advances in tabletting technology, especially the introduction of number of directly compressible excipients. The spherically agglomerated crystals can be prepared in tablet form or compounded directly into a pharmaceutical system without further processing such as granulation.

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About Authors:

Dr.A.V.Yadav

Working as Head, Department of Pharmacy, Govt.College of Pharmacy, Vidayanager, Karad, Dist: Satara, Pin code- 415124, ( Maharashtra ). INDIA .

Email: avyadav03@rediffmail.com, Phone No: 02164271832,Cell No:09890601832

Mr.Venkat B.Yadav

PhD student, working on spherical crystallization technology under the guidance of Dr.A.V.Yadav in Govt.College of Pharmacy, Vidayanager, Karad, Dist: Satara, Pin code- 415124, ( Maharashtra ). INDIA .
E-Mail: venkat_yadav3@rediffmail.com, Cell No. 09925099784.