INTRODUCTION:

In the mid-20th century, the field of preformulation studies began to take shape, laying the foundation for the rational development of drug dosage forms. Preformulation testing, a crucial initial step in this process, involves a thorough exploration of the physical and chemical properties of a drug substance in isolation as well as when combined with excipients.

Its overarching goal is to provide formulators with valuable insights to create stable, bioavailable dosage forms suitable for large-scale production.

Preformulation investigations aim to gather a comprehensive array of data, spanning physicochemical attributes, mechanical properties, and biopharmaceutical characteristics of the drug substance, excipients, and even the packaging materials involved^1,2.

For a successful formulation development journey, it is imperative to ascertain the key physicochemical properties of a novel drug entity during its early discovery stages. This knowledge is instrumental in selecting the most promising molecule for further formulation development. Once an optimal candidate molecule is identified for clinical testing, it becomes essential to delve into the biopharmaceutical aspects of the drug substance concerning its in vivo absorption and disposition. This insight guides the formulation choices made to maximize the drug's bioavailability. As the formulation advances to clinical trials, meticulous examination of its mechanical properties becomes critical to ensure consistent, efficient, and reproducible large-scale manufacturing³.

Beyond its role in formulation development, preformulation studies serve as an invaluable aid during the drug discovery phase by aiding in lead identification. To evolve into a viable drug, a new chemical entity must exhibit not only potency and selectivity but also optimal biopharmaceutical properties. Preformulation studies are instrumental in evaluating the 'drug ability' of a molecule, making them a pivotal decision-making tool in both drug discovery and development. A comprehensive grasp of physicochemical properties and their influence on biological performance not only aids in the selection of potential lead molecules but also facilitates the identification of challenges in drug delivery.

In summary, preformulation studies are a cornerstone of modern pharmaceutical science, providing the essential building blocks for the development of safe, effective, and scalable drug formulations while also playing a decisive role in lead identification and drug discovery.

Preformulation Parameters:

A. PHYSICAL CHARACTERISTICS:

1) Organoleptic properties

2) Bulk characteristics

a) Solid state characteristics

b) Flow properties

c) densities

d) compressibility

e) crystalline

f) polymorphism

g) hygroscopicity

3) Solubility analysis

a) Ionization constant (Pka)

b) Partition co-efficient

c) Solubilisation

d) Thermal effect

e) Common ion effect (Ksp)

f) Dissolution

4) Stability analysis

a) Solution-state stability

b) Solid-state stability

c) Drug-excipients compatibility

B. CHEMICAL CHARACTERISTICS:

1) Hydrolysis

2) Oxidation

3) Photolysis

4) Polymerization

MATERIALS AND METHODS:

1. Melting point determination:

Melting point of drug sample was determined by using melting point apparatus. A few quantity of drug sample was taken and placed in a thin walled capillary tube; the tube was approximately 10-12cm in length with 1mm in diameter and closed at one end. The capillary which contain sample was placed in melting point apparatus and heated and when drug sample was melted the melting point of sample powder was noted⁴.

2. pH Determination:

This was done by shaking a 1% w/v dispersion of the sample in water for 5min and the pH determination using a digital pH meter.

3. Loss on Drying:

Weigh about 1.0g of sample, dry it at 105ºC for 3~4hrs.Cool for 30±5 minutes. It loses not more than 0.5% of its weight. Calculate as following formula:

Loss on Drying %= m1-m2/ m1-m×100% Where:

m1── the weight of weighing bottle and sample

m2── the weight of sample and weighing bottle after drying m ── the weight of weighing bottle dried to constant weight⁵.

4. Determination of solubility:

a. Qualitative Solubility:

Qualitative solubility analysis of drugs were done by dissolving 5 mg of drug in 5 ml of distilled water and different solvents such as HCl (0.1N), Saline phosphate buffer (pH 7.4), Phosphate buffer(pH 6.8), ethanol, acetone and chloroform were used to determine the solubility of drug.

b. Quantitative Solubility:

Quantitative solubility analysis of drugs were done by 5 ml each solvent and drug in gm(s) into the solvent till saturation of solvent. Different solvents were used for the solubility determination like distilled water, phosphate buffer (pH 7.4), Phosphate buffer (pH 6.8), HCl (0.1N) and NaOH (0.05N). This is done to determine the capacity of the solvent for dissolving the drug in it. The concentration of drug is measured by UV spectrophotometer.

5. Determination of bulk density, tapped density:

The bulk density of ticagrelor was determined by the three tap method. 10g of ticagrelor powder was carefully introduced into a 100ml graduated cylinder. The cylinder was dropped onto a hard wood surface 50times from a height of 1inch at an interval of 2 seconds. The bulk density was obtained by dividing the weight of the sample by volume of the sample contained in the cylinder. Reciprocal of bulk density or the specific bulk volume gave the bulkiness. The percent compressibility index (I) of the ticagrelor was calculated using following formula and the results are given in Table. I= (1 – V/V0) x100

Drug Identification Studies:

1. FTIR Study:

FTIR study of drug sample and identification studies was performed by potassium bromide (KBr) dispersion method (Shimadzu). Samples were prepared with KBr pellets (2 mg sample in 200mg KBr) with a hydrostatic force of 5.2 N cm-2 for 3 minutes. The scanning range was 400 to 4000 cm-1 and the resolution was 4 cm-1.

2. UV-visible spectrophotometric study:

Weighed 10mg of Ticagrelor and dissolved in 10ml of pH 6.8 phosphate buffer solution (1000µg/ml). From this solution 1ml was taken and diluted to 10ml with PBS to get a solution containing 100µg/ml. From this 1ml was diluted to 10ml to get working standard solutions of 10μg/ml. This solution was scanned between 200-400 nm and an absorption maximum was determined and compared with literature value.

3. Preparation of calibration curve in phosphate buffer (pH 6.8):

Weighed 10mg of Ticagrelor and dissolved in 10ml of pH 6.8 phosphate buffer solution (1000µg/ml). From this solution 0.5ml, 1ml, 2ml, 3ml, 4ml was taken and diluted up to 100ml using pH 6.8 phosphate buffer solution to obtain a working standard solution of 5- 40µg/ml. The prepared concentrations were analyzed in UV-Visible spectroscopy at 255nm.

4. Linearity:

The linearity of the calibration curve was estimated by plotting the graph in between absorbance (nm) (y) versus concentration (µg/ml) (x) of Ticagrelor in the concentration range 5-40µg/ml. A calibration curve was prepared by measure the absorbance at 255nm. The Statistical evaluation parameter like as the slope, intercept, regression coefficient, standard deviation (R2), and relative standard deviation were determined.

UV Spectrophotometric studies:

The absorbance maximum was found to be 255nm in phosphate buffer pH 6.8⁶.

Drug Stability Studies:

Solid State Stability:

The primary objective is to identify the stable storage conditions for API in solid state and identify the possible deterioration of drug on storage conditions the solid state study may be affected by changes in purity and Crystallinity during storage.

Weighed samples (250mg) were paced in vials and exposed at various condition of temperature, humidity in stability chamber at room temperature, 40±2 and 75±5% humidity conditions and at refrigerator for upto 4 weeks and were after studied for physical tests in 4th, 8th and 12th week for various Organoleptic and FTIR study.

Photo stability Studies:

For photo stability studies drug samples both in solid state form were paced in different containers i.e. pain glass and amber colored glass and kept in sunlight for 12 weeks and were further analysed for Organoleptic studies, FTIR and UV absorbance.

Liquid State Stability:

The primary objective is to identify the stable storage conditions for API in solution form and identify the possible deterioration of solution form of drug on storage conditions that may be due to hydrolysis, oxidation etc. Weighed samples (50mg) were dissolved in phosphate buffer (Ph 6.8) and paced in vials and closed properly and were exposed at room temperature upto 12 weeks and were after studied for physical tests in 4th, 8th and 12th week by UV Spectroscopic study⁷.

RESULT:

Table 1: Melting point

Sr. No	Melting point °C	Mean
1.	136	138.6
2.	140
3.	140

Table 2: Loss on drying:

Weight of Bottle	29.31
Weight of Bottle + Sample	29.41
After drying	29.40

Table 3: pH

Sr. No	Reading	Mean
1.	7.5	7.5
2.	7.6	7.5

Table 4: Solubility:

Solvent	Solubility of drug
Distilled water	Insoluble
0.1 N HCl	Insoluble
7.4 pH buffer	Insoluble
Ethanol	Very soluble
Methanol	Very soluble
Chloroform	Freely soluble
Acetone	Very soluble

Table 5: Stability:

Sr. No	Condition	Result
1.	Room temperature	Colour: pale pink Odour: no odour
2.	Refrigerator (3 to 4 degree Celsius)	Colour: pale pink Odour: no odour
3.	Photostability	Colour: pale yellow Odour: no odour
4.	Original API	Colour: pale pink Odour: no odour

UV-visible spectrophotometrically study:

Figure 1 . H₂O₂ graph

Figure 2 . TGL 0.1 N HCl graph

Figure 3: Ticagrelor lamda max

DISCUSSION:

Preformulation for drugs like ticagrelor is pivotal in the pharmaceutical development process. Understanding its physicochemical properties, including solubility, stability, and particle characteristics, is fundamental to ensuring its efficacy and safety. Compatibility with excipients, stability under varying conditions, and particle size considerations are crucial for formulation. Additionally, assessing dissolution, pH-dependent solubility, hygroscopicity, and salt selection optimizes bioavailability and shelf-life. Compatibility with manufacturing processes is vital for consistent production, and toxicity studies are imperative to guarantee human safety. These preformulation steps collectively lay the foundation for successful drug development.

CONCLUSION:

The preformulation stage for a drug like ticagrelor involves a thorough investigation of its physicochemical properties, compatibility with excipients, stability, solubility, and various other factors. This information is crucial for the development of safe and effective drug formulations, ensuring that the drug can be manufactured consistently, and that it will perform as intended in the human body.

ACKNOWLEDGMENTS:

The authors would like to thank Kamla Nehru College of Pharmacy Butibori, Nagpur for their kind support during all other studies.

REFERENCES:

1. Prasanna Kumar et al, An Overview on Preformulation Studies, Indo Am. J. Pharm. Sci. 2015; 2(10).

2. Albert, A.A. and Serjeant, E. P. Ionization Constants of Acids and Bases.Wiley, New York. 1984

3. Yalkowiski, S.H. and Roseman, T.J. Industrial Pharmacy Fourth edition by Lachman and Lieberman’s 1981515 pg.

4. Seyda A. A Non-steroidal anti-inflammatory drug, Aceclofenac, FABAD Journal of Pharmaceutical Science. 2010; 35: 105-118.

5. Chandel N. Co-crystalization of Aceclofenac and Paracetamol and their characterization, International Journal of Pharmacy and Life Science. 2011; 2(8): 1020- 1028.

6. Jayanthi B, Madhusudhan S. Preformulation Characterisation, Designing and Formulation of Aceclofenac Loaded Microparticles. International Journal of Drug Development and Research. 2012; 4(3):186-196

7. Lachman Leon, Liebermann AH. The Theory and Practice of Industrial Pharmacy CBS Publishers and Distributors Pvt Ltd. Indian Edition: 2010: 193-194.

Received on 24.02.2024 Modified on 09.05.2024

Asian J. Res. Pharm. Sci. 2024; 14(3):227-230.

DOI: 10.52711/2231-5659.2024.00037