**4.2 Crystalline vs amorphous form**

Amorphous drugs have randomly arranged molecules or atoms in the molecular lattice. Typical amorphous forms are obtained by techniques like precipitation, rapid cooling after melting, and lyophilization. One of the most important advantages associated with amorphous form is the higher solubility and hence the higher dissolution rate. More often than not drugs with low water solubility lead to poor bioavailability and variable clinical response. So, polymorphic form may overcome this problem


#### **Table 2.**

*Correlation of solubility and permeability with BCS class and associated approach in formulation development.*


#### **Table 3.**

*Solubility description.*

with main challenge of stability. The associated disadvantage is the reduced stability in comparison to crystalline form, so upon storage, amorphous forms tend to revert to more stable form. But the risk-to-benefit ratio remains in the favor of amorphous from and hence is more preferred for product development. For example, novobiocin when administered in crystalline form showed no therapeutic activity, while amorphous from showed better absorption from gastrointestinal tract with significant therapeutic response [11]. Crystalline form is characterized by regular spacing between molecular lattices in three-dimensional structure. One of the striking advantages associated with this form is the impeccable stability at a cost of lower water solubility than amorphous form. For example, Penicillin G as sodium or potassium salt in crystalline form has the better stability and hence stable and better therapeutic response in comparison to amorphous form. Various techniques are available to study crystallinity like X-ray, differential scanning microscopy, differential thermal analysis, hot stage microscopy, and the most important one that is scanning electron microscopy.

#### **4.3 Polymorphism and pseudo polymorphism**

Polymorphism is the ability of a compound to crystallize as more than one distinct chemically identical crystalline species with different internal lattices or crystal packing arrangement. Type of crystalline species generated depends on temperature, solvent, and time. Polymorphs are chemically same but mainly differ with respect to physical and pharmaceutical properties. As different types of polymorphs exhibit different types of solubility, stability, and therapeutic activity, it has become mandatory to have preliminary and exhaustive screening to identify all the polymorphic crystal forms for each drug. Similarly, chloramphenicol palmitate exists in three different polymorphic forms, namely, A, B, and C. Form

**13**

*Preformulation Studies: An Integral Part of Formulation Design*

B has higher solubility and better dissolution profile, while form A is more stable one but low serum concentration was observed. During formulating suspension of an anthelmintic drug oxyclozanide, transformation of unstable polymorph to more stable leads to different crystal size and causes caking. In case of creams, crystal growth leads to gritty texture and incase of suppositories one can observe different melting behaviors and leads to formulation instability [12]. When solvent molecules are incorporated into structure of drug molecule, it is known as solvate. When water is incorporated as solvent in the structure, they are termed as hydrates. Pseudopolymorphs are the different crystal form of solvates. This phenomenon is also referred to as solvomorphism. For example, during synthesis of ethinylestradiol, crystallization of final product is achieved by using solvents like acetonitrile, chloroform, methanol, and water. As a result, four different solvates are generated. Differentiation of pseudopolymorphs can be studied by hot stage microscopy (melting behavior). True polymorphs melt slightly and form a globule, while pseudopolymorphs give bubble in the system due to generation of

Two different types of polymorphs are well defined and are known as "monotropic polymorphs" and "enantiotropic polymorphs." Monotropic polymorph can be reversibly changed into another form by change in temperature and pressure and the latter involves one-time transition into another form. With respect to stability and solubility, again polymorphs can be classified as stable and metastable polymorphs. Stable polymorph is one of the most physically stable polymorphic forms and has highest melting point, lowest energy, and least aqueous solubility, while metastable polymorph refers to forms other than stable polymorph and has highest energy, low melting point, highest aqueous solubility, and hence shows better bioavailability. Metastable polymorphs have wider application in developing formulation but still only one-tenth of metastable forms are having practical use as they suffer from the stability issues [13].

Hygroscopicity can be defined as the capacity of a compound to absorb atmospheric moisture. Amount of moisture absorbed depends on atmospheric conditions and surface area. Deliquescent substance absorbs moisture to a greater extent and liquefies itself. The main reason behind study of this property is because changes in the moisture level can influence chemical stability, flowability, and

after being stored at 25°C at relative humidity of 80% for 24 hours.

weight is greater or equal to 0.2% but less than 15% w/w.

analysis (TGA), Karl Fischer titration, and gas chromatography.

In European pharmacopeia, hygroscopicity is described by four different classes

• Slightly hygroscopic: After abovementioned storage condition, if overall increase in weight is greater or equal to 0.2% but less than 2% w/w.

• Hygroscopic: After abovementioned storage condition, if overall increase in

• Very hygroscopic: After abovementioned storage condition, if overall increase

For this study, samples under analysis are exposed to range of controlled relative humidity prepared with saturated aqueous salt solutions (**Table 4**). One can link flowability and relative humidity by amount of moisture uptake (**Table 5**).

Moisture level uptake can be monitored by techniques like thermogravimetric

*DOI: http://dx.doi.org/10.5772/intechopen.82868*

vapor or gas from entrapped solvent.

**4.4 Deliquescency vs hygroscopicity**

compressibility to a greater extent.

in weight is greater than 15% w/w.

### *Preformulation Studies: An Integral Part of Formulation Design DOI: http://dx.doi.org/10.5772/intechopen.82868*

*Pharmaceutical Formulation Design - Recent Practices*

with main challenge of stability. The associated disadvantage is the reduced stability in comparison to crystalline form, so upon storage, amorphous forms tend to revert to more stable form. But the risk-to-benefit ratio remains in the favor of amorphous from and hence is more preferred for product development. For example, novobiocin when administered in crystalline form showed no therapeutic activity, while amorphous from showed better absorption from gastrointestinal tract with significant therapeutic response [11]. Crystalline form is characterized by regular spacing between molecular lattices in three-dimensional structure. One of the striking advantages associated with this form is the impeccable stability at a cost of lower water solubility than amorphous form. For example, Penicillin G as sodium or potassium salt in crystalline form has the better stability and hence stable and better therapeutic response in comparison to amorphous form. Various techniques are available to study crystallinity like X-ray, differential scanning microscopy, differential thermal analysis, hot stage microscopy,

**Descriptive term Part of solvent required for one part of solute**

*Correlation of solubility and permeability with BCS class and associated approach in formulation* 

**Solubility Permeability Approaches in formulation development**

Class 2 Low High Use techniques to improve surface area or improving

solubility by addition of cosolvents or surfactants

Very soluble Less than 1 Freely soluble 1–10 Soluble 10–30 Sparingly soluble 30–100 Slightly soluble 100–1000 Very slightly soluble 1000–10,000 Practically insoluble or insoluble 10,000 or more

Class 1 High High Conventional solid oral dosage form

Class 3 High Low Use of permeability enhances Class 4 Low Low Use approaches of classes 2 and 3

Polymorphism is the ability of a compound to crystallize as more than one distinct chemically identical crystalline species with different internal lattices or crystal packing arrangement. Type of crystalline species generated depends on temperature, solvent, and time. Polymorphs are chemically same but mainly differ with respect to physical and pharmaceutical properties. As different types of polymorphs exhibit different types of solubility, stability, and therapeutic activity, it has become mandatory to have preliminary and exhaustive screening to identify all the polymorphic crystal forms for each drug. Similarly, chloramphenicol palmitate exists in three different polymorphic forms, namely, A, B, and C. Form

and the most important one that is scanning electron microscopy.

**4.3 Polymorphism and pseudo polymorphism**

**12**

**Table 3.**

**BCS class**

**Table 2.**

*development.*

*Solubility description.*

B has higher solubility and better dissolution profile, while form A is more stable one but low serum concentration was observed. During formulating suspension of an anthelmintic drug oxyclozanide, transformation of unstable polymorph to more stable leads to different crystal size and causes caking. In case of creams, crystal growth leads to gritty texture and incase of suppositories one can observe different melting behaviors and leads to formulation instability [12]. When solvent molecules are incorporated into structure of drug molecule, it is known as solvate. When water is incorporated as solvent in the structure, they are termed as hydrates. Pseudopolymorphs are the different crystal form of solvates. This phenomenon is also referred to as solvomorphism. For example, during synthesis of ethinylestradiol, crystallization of final product is achieved by using solvents like acetonitrile, chloroform, methanol, and water. As a result, four different solvates are generated. Differentiation of pseudopolymorphs can be studied by hot stage microscopy (melting behavior). True polymorphs melt slightly and form a globule, while pseudopolymorphs give bubble in the system due to generation of vapor or gas from entrapped solvent.

Two different types of polymorphs are well defined and are known as "monotropic polymorphs" and "enantiotropic polymorphs." Monotropic polymorph can be reversibly changed into another form by change in temperature and pressure and the latter involves one-time transition into another form. With respect to stability and solubility, again polymorphs can be classified as stable and metastable polymorphs. Stable polymorph is one of the most physically stable polymorphic forms and has highest melting point, lowest energy, and least aqueous solubility, while metastable polymorph refers to forms other than stable polymorph and has highest energy, low melting point, highest aqueous solubility, and hence shows better bioavailability. Metastable polymorphs have wider application in developing formulation but still only one-tenth of metastable forms are having practical use as they suffer from the stability issues [13].
