Keywords

1.1 Introduction

The branch of practical chemistry which deals with identification, detection, quantification, qualification, and purification of a substance, separation of constituents of a compound, and identification of structure of chemical compounds is called pharmaceutical analysis. The substance which is to be analyzed may be a single isolated compound or mixture of different compounds or may be present in any dosage form. The pharmaceutical products contain those substances which may be originated from natural sources such as animals, plants, microorganisms, and minerals or synthetic sources [1]. In a comprehensive way, pharmaceutical analysis can be defined as it is an application of the processes that are involved in order to determine the identity of a drug (single or compound) either in its bulk form or pharmaceutical dosage form. To analyze the pharmaceutical substances, various testing have to be performed such as physical, chemical, and microbiological testing [2].

Pharmaceutical analysis can be categorized into two types: qualitative analysis and quantitative analysis. Qualitative analysis is a type of analysis in which the presence of components or impurities is determined which may be expected in a compound or substance. Quantitative analysis is a type of analysis in which the quantity of a drug or substance present in bulk form or in a pharmaceutical formulation is determined. The quality of pharmaceutical substance can be judged by using the correct analytical method. The method should be able to identify the drug in the bulk. The method has capability to determine the stated contents of a drug in the formulation within acceptable limit. It describes the stability of drug content in the formulation and shelf life (the period in which product retains its physical, chemical, microbial, and therapeutic characteristics). It helps to determine the dissolution rate and bioavailability of drug in the body. It should be able to ensure that quality and quantity of drug in the formulation meet with official standards [3].

The pharmaceutical analysis is performed to determine the stability of drug. The stability of pharmaceutical products can be defined as ability of the product to retain its physical, chemical, and microbiological properties and efficacy throughout its shelf life in a container [4]. Mostly, the shelf life of pharmaceutical products is approximately from 3 to 5 years. The drug should maintain its concentration within specified limit and not reduce more than 95% of its original value [5]. Pharmacists are responsible for determining the impact of chemical degradation on the pharmaceuticals. For preparation of sterile products and proper storage conditions of the pharmaceuticals and for determining the shelf life, it is necessary to have knowledge of chemical kinetics. Chemical kinetics deals with the series of reactions involved in the chemical degradation with respect to time [6]. Automatic kinetic methods are used for analysis of many pharmaceuticals because they have significantly increased the quality of testing and reduced the timing [7].

1.2 Drug Stability

The stability analysis of pharmaceutical products is a very complicated process that requires large amount of money, consumption of time, and high level of scientific expertise. The stability analysis has been performed to maintain the quality, efficacy, potency, and safety of the drug. In order to maintain the stability of drugs, care must be taken during the developmental process. The main steps involved in the development of the drug products are pharmaceutical analysis and stability studies of the drug products in order to maintain its quality and efficacy [8].

Stability of pharmaceutical can be defined as the capability of pharmaceutical products to retain its physical, chemical, microbiological, and therapeutic characteristics within the limits as specified by monograph or official standard books during the period of shelf life [9]. Stability studies are performed to evaluate the impact of environmental factors on the formulation, drug substance, or pharmaceuticals. Stability testing helps to determine the shelf life and storage conditions of the products and instructions for labeling on the containers of the products. The stability testing is also very important to generate the data for approval of drug formulation from regulatory authority [8].

1.3 General Objectives of Drug Stability

The basic purpose of stability testing is to determine how the quality of the drug product changes with the passage of time under the different environmental conditions such as humidity, temperature, and light and also to establish the re-test period of the drug products, determine shelf life of the drug products, and determine the storage conditions of the drug products [10]. The stability programs include the study of factors that influence the quality of the products, such as interactions of ingredients with excipients, packing material, and container closure system. The interaction of two or more ingredients is also studied in fixed-dose combination. The stability studies provide information about shelf life, storage conditions, and compatibility of different ingredients in dosage form. The guidelines for stability testing are provided by WHO [11].

1.4 Types of Drug Stability

There are different types of stability such as physical, chemical, microbiological, toxicological, and therapeutic stability. The different types of stability and conditions which are necessary for maintaining the quality of drug are tabulated in comprehensive form in Table 1.1. The stability of drug product significantly depends upon environmental conditions and particular dosage form of drug products. The different dosage form of the pharmaceutical products is given in Fig. 1.1.

Table 1.1 Types of stability and conditions
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Fig. 1.1
figure 1

Types of dosage forms of pharmaceutical products

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1.4.1 Physical Stability

In physical stability, the physical states are significantly considered for the stability of drug products. The physical properties of drug such as appearance (size, shape, and color), uniformity, palatability, and dissolving and suspending ability should be maintained throughout the period of its shelf life. The physical changes depend upon the physical characteristics of the drug products such as particle size, texture, melting point, polymorphic behavior, and morphology. For liquid dosage forms, the physical stability of the drug products depends upon physical properties such as appearance, discoloration, polymorphism, changes in viscosity, adsorption of drug, precipitation, and growth of microorganisms. These changes in the physical characteristics can cause destabilization of the drug products.

1.4.2 Chemical Stability

All the active ingredients present in the dosage form have the ability to retain their chemical integrity and potency within the specified limit that is labelled on the container or specified in standard books. Drug products have diverse structure and undergo many different degradation pathways. These pathways may include dehydration, oxidation, photodegradation, isomerization, hydrolysis elimination, and complicated interactions with excipients [12] as shown in Table 1.1.

1.4.3 Microbiological Stability

The products should have the ability to retain their sterility/resistance for the growth of microorganism during its shelf life according to the specified limitations. Antimicrobial agents present in the products should retain their activity. Many drug products contain preservatives for protection of drug substances from spoilage. Because contaminated drug products have severe effects on the consumers, that’s why the activity of the preservative should be retained during its shelf life. The biological activity of the preservatives must be assessed [13]. Contamination of pharmaceuticals is a critical issue, especially moisture-containing and polymer-containing dosage, because they are the major source for growth of microorganisms. To protect our pharmaceutical product from contamination, we must follow good manufacturing procedures [14]. There are different sources of microbial contamination, which are given in Table 1.2.

Table 1.2 Sources of microbial contamination
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1.5 Analytical Techniques

In the pharmaceutics, for development of drug substances, it is necessary to conduct analytical investigation of raw materials, bulk drug substances, intermediate products, finished drug products, degraded products, and many biological samples having drug and their metabolites. For conducting the pharmaceutical analysis, many analytical techniques are used such as titrimetric analysis, chromatography, electrophoresis, spectrometry, high-performance liquid chromatography (HPLC), and many other electroanalytical techniques. These techniques are also mentioned in the compendial monographs for characterization of quality of bulk drug substances by specifying the range of active ingredients’ content in drug formulation [15].

1.6 Kinetic Methods of Analysis

These methods have been developed in 1950 for analysis of pharmaceuticals. These methods have been developed due to advancement in the principles, progress in automated instrumentation techniques, understanding of chemistry, methods of data analysis, and application in analytics. Use of kinetic approach for analysis of pharmaceuticals has many advantages as compared to traditional equilibrium approach [15]. Kinetic methods are used for detecting and measuring the change in the concentration of reactants via signal change with the passage of time when sample and reagents are mixed mechanically or manually. In pharmaceuticals, various techniques such as fixed-time and initial rate methods are frequently used for determination of drug in the formulation [16].

In kinetic methods, different automated techniques are commonly used such as stopped-flow system and continuous addition of reagent (CAR) technique which are based upon open system [15]. Some of drugs are estimated by CAR technique by using photometric technique [17] and fluorometric technique [18]. Catalyst is used to accelerate the chemical reaction and it is feasible for equilibrium state and rate of a reaction. The micellar media can be used in kinetic model to increase the reaction via micellar catalysis. This has significance to improve sensitivity and selectivity and lessen the time for analysis of analyte [19].

In pharmaceutical analysis, multicomponent kinetic estimations are also widely used in analysis of pharmaceutical formulation. The multicomponent kinetic estimations are also referred to as differential rate methods [20]. There are also two approaches, H-point standard addition method and kinetic wavelength-pair method, used for dealing with overlapping spectrum of different components in the binary mixture [15].

1.7 Protocol for Stability Studies

The protocols for stability studies include the following key points:

  1. 1.

    Information on the tested batches, including the chemical formula

  2. 2.

    Composition of the dosage form

  3. 3.

    Packing of finished drug products

  4. 4.

    Literature

  5. 5.

    Specifications of finished drug products

  6. 6.

    Analytical methods for stability study

  7. 7.

    Schedule for stability testing

  8. 8.

    Tabulated test result with the specified limitations

  9. 9.

    Analysis of data

  10. 10.

    Determination of shelf life

  11. 11.

    Commitment for post approval

1.8 Routes of Drug Degradation

The drug degradation can follow physical or chemical pathways depending upon the factors.

1.8.1 Physical Degradation

Many ingredients present in the dosage form exist in different microscopic physical state such as hydrates, solvates, and crystalline states. Many excipients change their state to convert into more stabilized form. The rate of reaction depends upon potential, free energy difference, and energy barrier. Examples of drugs that undergo physical degradation by different pathways are given in Table 1.3.

Table 1.3 Examples of drugs that undergo physical degradation
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1.8.2 Crystallization of Amorphous Drugs

Pharmaceutical dosage form is formulated in such a way that poorly water-soluble drug is present in its amorphous state. Because a substance is more soluble in the amorphous phase than crystalline state and crystalline substances have lower free energy as compared to amorphous state, amorphous substances have the ability to undergo a chemical reaction to achieve a more thermodynamically stable state. For example, amorphous nifedipine, under high humidity conditions, is coprecipitated with polyvinylpyrrolidone due to partial crystallization. As a result, changes in the solubility and dissolution may occur.

1.8.3 Transitions in Crystalline States

There are various crystalline forms of a drug called as polymorphs. The various forms of polymorphs have different potential and free energy at different temperature. The transition between different polymorphs occurs depending upon the temperature and humidity. The solubility and dissolution of the drug substance change due to transition in polymorphic states. For example, literature shows that existence of two polymorphic forms of benoxaprofen and three forms of bromovalerylurea has been observed at different temperature.

1.8.4 Moisture Adsorption

Mostly moisture is adsorbed on the surface of solid pharmaceuticals that has significant effect on the physical stability of the drug and excipients such as appearance, dissolution, and solubility. For example, if hydrophilic excipients are added in the aspirin, then it can adsorb the moisture from the environment.

1.8.5 Vaporizing

Many components present in the pharmaceuticals can easily sublime as a result of change in the activity of the substances. For example, nitroglycerine, present in sublingual tablets, has ability to vaporize during storage. The vaporizing ability of nitroglycerin is inhibited by the addition of water-soluble and non-volatile fixing agent, polyethylene glycol.

1.8.6 Formation and Growth of Crystals

Crystals present in the pharmaceuticals are not considered static. Crystals may increase or decrease in size by travelling across the medium. The medium may be a liquid or gaseous phase through which molecules can sublime. Some ingredients may recrystallize or sublime from pharmaceutical dosage forms such as tablets or granules. The crystallization is increased at high temperature in porous tablets. For example, crystallized formation has been observed in the ethenzamide tablets which is confirmed by apparent zero-order kinetics. Crystallization of ethenzamide is enhanced at low and high humidity [21].

1.8.7 Chemical Routes of Drug Degradation

Most of the drugs may undergo degradation by different chemical reactions. Examples of drugs that undergo chemical degradation by different pathways are given in Table 1.4.

Table 1.4 Examples of drugs that undergo chemical degradation
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1.8.8 Solvolysis

Due to the presence of a solvent, drugs undergo degradation due to a chemical reaction with the solvent. The most commonly used solvent is water, but a co-solvent may be used in pharmaceuticals. The solvents may act as a nucleophile and have ability to attack on the nucleophile. The most commonly used drugs which undergo attack mostly contain carbonyl compounds. For example, the drugs containing beta-lactam ring are more susceptible to hydrolysis than its linear analogue.

1.8.9 Oxidation

Oxidation reactions play a very important role in the degradation pathway of the drugs. Many drugs undergo autoxidation reaction which occurs due to presence of free atmospheric oxygen called free radical reaction. To protect our pharmaceutical product, there is a need to control the concentration of oxygen in the aqueous solution. Sensitivity of the drug product to oxygen is determined by high oxygen tension. The mechanism by which oxidation takes place involves different pathways such as initiation, propagation, and termination. Oxidation reactions may also be catalyzed by the acid and base. For example, polyethylene glycol suppository base contains hydroperoxides, which are responsible for oxidation of codeine into codeine-N-oxide.

1.8.10 Photolysis

Most of the drugs undergo degradation due to the presence of light. The molecules absorb energy from radiation and undergo photolytic reaction. If this energy is enough to cause the activation of reaction, then degradation of molecule is possible. The molecules containing п electron absorb the wavelength of visible region and as a result degrade. Mostly drugs degrade by absorbing the radiation of wavelength below 280 nm and above 400 nm. But pharmaceutical products must be protected by suitable packing from photodegradation. For example, sodium nitroprusside, administered intravenously to manage hypertension, in the presence of aqueous solution undergoes photodegradation.

1.8.11 Dehydration

Removal of water from a molecule is called dehydration. The molecule undergoes dehydration; as a result, double bond is formed and participates in the electronic resonance with the neighboring atoms. For example, tetracycline and prostaglandin E2 undergo dehydration by eliminating a molecule of water from its structure.

1.8.12 Racemization

Racemization must be considered in the drug development process. Different kinds of enantiomers of a pharmaceutical compound are significantly different from each other by means of absorption, distribution, metabolism, and elimination. For example, a pilocarpine converts into carbanion by racemization process which is further stabilized by enolate ion. Pilocarpine is also degraded due to hydrolysis of lactone group.

1.8.13 Incompatibilities

A pharmaceutical dosage form contains active ingredient and number of excipients. A chemical incompatibility may occur in active ingredients and adjuvants. For example, in intravenous admixture, inactivation of cationic aminoglycosides occurs due to presence of anionic penicillin. Glycation of lysine vasopressin may occur due to presence of reducing sugar in aqueous and non-aqueous solvent [22].

1.9 Chemical Kinetics

It deals with chemical reaction rate. Chemical kinetics is very helpful for the identification of mechanism by which drug degrades and how to stabilize it.

1.9.1 Rate of Order of Reactions

The rate of a reaction is defined as the amount of reactant which is lost per unit time or concentration of a degraded product. The reaction rate is explained by a rate equation. For example, a reaction is given below:

$$ aA+ bB\to mM+ nN $$

where A and B are reactants and M and N are products. Stoichiometric constants are a, b, m, and n, which express the number of moles that take part in the chemical reaction.

1.9.2 Expression of Rate Equation

The rate equation can be expressed as a decrease in the concentration of reactant and an increase in the formation of the product:

$$ {dC}_A/ dt={dC}_B/ dt=-k\ {C^a}_A\ {C^b}_B $$

where k is constant and negative sign indicates that there is decrease in the concentration of the reactant.

1.9.3 Order of Reaction

It is the sum of exponents of the concentration terms in the rate expression. The order of a reaction can be defined mathematically as:

$$ n=a+b $$

A reaction is said to be second-order reaction if the value of a and b is 1, assumed to be first-order reaction in relation to a and also considered as first-order reaction in relation to b. Value of a or b may be fraction or integers.

1.9.4 Simple Order Kinetics

Simple order reactions include zero, first, and second order of a reaction. These reactions are considered to be important for pharmaceutical stability studies. For stability study, their mathematical presentations are encountered.

1.9.5 Zero Order of Reaction

In this reaction, the rate of a reaction is not depending upon the concentration of the reactants. The rate at which the concentration of reactant and product changes is constant in zero-order reaction. Many decomposition reactions occur in the solid state or in the suspension form may undergo zero-order reaction. The reaction rate is depending upon many factors such as interfacial surface area and absorption of light. The rate equation of zero-order reaction is expressed as:

$$ {\displaystyle \begin{array}{c}- dA/ dt={k}_0\\ {}\mathrm{OR}\\ {}- dA= dt\ {k}_0\end{array}} $$

where k0 is a zero-order constant.

The concentration of A decreases with respect to time as a reaction proceeds:

$$ {\left[A\right]}_t={\left[A\right]}_0- kt $$

where [A]t is concentration of A at time t and [A]0 represents the concentration of A at time 0 [23].

1.9.6 First-Order Reaction

The rate of a reaction for first order is directly proportional to concentration of one reactant. Decomposition reactions of many ingredients present in the solid phase and in the suspension follow the first-order reaction. In this order of reaction, concentration of the reactant decreases exponentially with time, and rate of reaction progressively slows down:

$$ \mathrm{Rate}=-d\left[A\right]/ dt=\left[A\right]k $$

The concentration time profile of the species that are involved in a first-order reaction follows an exponential decay to limiting value, but products follow an exponential increase to a different limiting value:

$$ {\displaystyle \begin{array}{c}{\left[A\right]}_t={\left[A\right]}_0-\exp \left(- kt\right)\\ {}{\left[C\right]}_t={\left[A\right]}_0\left[1-\exp \left(- kt\right)\right]\end{array}} $$

The half-life of a reaction can be defined as the time required for a 50% decrease in the concentration of the reactant from its initial concentration and expressed as t1/2. Similarly if concentration of reactants decreases to 95 and 90%, then half-life for that reactions is expressed as t95 and t90. These quantities can be determined by using these equations, if rate constant is known:

$$ {\displaystyle \begin{array}{c}{t}_{1/2}=\ln\ 2/\mathrm{k}\\ {}{t}_{95}=\ln\ 0.95/\mathrm{k}\\ {}{t}_{90}=\ln\ 0.9/\mathrm{k}\end{array}} $$

For first order of reaction, the time required to lose 50% of drug from initial concentration is the same as concentration of drug is dropped from 50% remaining to 25%, from 25% remaining to 12.5%, and so on.

1.9.7 Second-Order Reaction

In second order of reaction, two reactants are involved in a reaction. In pharmaceutics, first order of a reaction is mostly observed, but in reality, they are second-order reaction. In these reactions, one reactant is in large excess; that’s why a change in the concentration of that reactant is negligible and assumed to be first order of reaction. The equation for a second order of reaction is given below:

$$ A+B\to C $$

The rate equation for this reaction is expressed as:

$$ \mathrm{Rate}=-d\left[A\right]/ dt=-d\left[B\right]/ dt=k\left[A\right]\left[B\right] $$

The rate of a reaction is a second order of a reaction but considered to be first order in relation to each reactant.

The concentration time profile for a second order of a reaction can be expressed as:

$$ 1/{\left[A\right]}_0-{\left[B\right]}_0\left[\ln {\left[A\right]}_t/{\left[B\right]}_t-\ln {\left[A\right]}_0/{\left[B\right]}_0\right]= kt $$

When, in a reaction, concentration of reactants A and B is the same, then concentration time profile can be expressed as:

$$ 1/{\left[A\right]}_t-1/{\left[A\right]}_0= kt $$

A graph is plotted between fraction remained and time to present the concentration time profile for a zero-, first-, and second-order profile. The rate equations and half-life for a simple reaction are shown in Table 1.5. For plotting concentration-time graph, rate constant is kept the same for all cases, and concentration of initial reactant is also kept identical for a graph and table [24] (Fig. 1.2).

Table 1.5 Expression of rate equations and concentration time profile for zero, first, and second order of reaction
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Fig. 1.2
figure 2

A graph presenting concentration time profile for zero, first, and second order of a reaction. (Adapted from Ref. [24])

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1.9.8 Complex Reactions

In the complex reactions, more than one step is involved. The kinetics of the reaction is estimated by rate equations which may be zero, first, and second order ultimately depending upon the scheme of reactions and rate constant magnitude. Some complex reactions are encountered whose schemes are discussed next.

1.9.9 Reversible Reactions

All chemical reactions are mostly reversible. For reversable rection, equilibrium constant is so large, but overall reaction is treated as virtually one-directional. A simple reversible reaction is shown below:

$$ A\underset{k2}{\overset{k1}{\rightleftarrows }}B $$

where k1 is first-order constant for forward reaction and k2 is the second-order rate constants for the reversible reaction. The rate equation of a reaction can be written as:

$$ \mathrm{Rate}=-d\left[A\right]/ dt=d\left[B\right]/ dt=k\ 1\left[A\right]-{k}_{-1}\left[B\right] $$

At the equilibrium stage, rate of forward reaction becomes equal to rate of reversible reaction. Then, the concentration of A and B does not change because forward and reversible reactions become equal:

$$ \mathrm{Rate}=-d\left[A\right]/ dt=d\left[B\right]/ dt=k\ 1{\left[A\right]}_{eq}-{k}_{-1}{\left[B\right]}_{eq}=0 $$

The eq in subscript indicates quantities of A and B species at equilibrium.

The equilibrium constant for this reaction can be expressed as:

$$ K={\left[B\right]}_{eq}/{\left[A\right]}_{eq}=k\ 1/{k}_{-1} $$

where K is equilibrium constant, ratio of rate of forward reaction, and rate of the reversible reaction.

1.9.10 Parallel Reactions

A drug can be degraded by more than one pathway involved in the reaction. As a result of degradation of drug, degraded products are formed. The reaction pathways may lead to identical or different degradants. Example for a parallel reaction is shown below:

figure a

Here k1 and k2 are the first-order rate constants for reactions A → B and A → C, respectively. The corresponding rate equation is:

$$ \mathrm{Rate}=-d\left[A\right]/ dt=k\ 1\left[A\right]+k\ 2\left[A\right]=\left(k1+k2\right)\left[A\right]={k}_{\mathrm{obs}}\left[A\right] $$

Here kobs is k1 + k2, which is the observed apparent first-order rate constant.

1.9.11 Consecutive Reactions

It is the reaction in which an intermediate product is formed from the initial reactant which is further converted into the final product. The example for a consecutive reaction is given below:

$$ {\displaystyle \begin{array}{ccccc}& k1& & k2& \\ {}A& \to & B& \to & C\end{array}} $$

In this simple first-order reaction, A is converted into C through an intermediate B.

The rate equation for this reaction can be written as:

$$ {\displaystyle \begin{array}{c}-d\left[A\right]/ dt=k\ 1\left[A\right]\\ {}\mathrm{or}\\ {}d\left[B\right]/ dt=k\ 1\left[A\right]-k\ 2\left[B\right]\\ {}\mathrm{or}\\ {}d\left[C\right]/ dt=k\ 2\left[B\right]\end{array}} $$

1.10 Factors Affecting the Stability of Drug

1.10.1 Temperature

Temperature has a significant effect on overall reactivity of a chemical reaction. The rate of a chemical reaction is enhanced by increasing temperature. In pharmaceutical analysis, for the stability studies of drug, regulatory authorities recommended a high temperature and extreme stress conditions. Arrhenius equation indicates the quantitative relationship between a reaction rate and temperature. According to estimation, the rate of a chemical reaction is doubled by rising 10 °C in temperature, and the reaction occurs rapidly, and the time of a reaction is decreased by a factor of 2.

1.10.2 Light

Light has the influence on the stability of drug via energy or thermal effect, which causes the oxidation of substances present in the drug formulation.

1.10.3 pH

pH has a significant influence on the decomposition of drug. Mostly drugs are stable at pH between 4 and 8. Solubility and degradation of weekly basic and acidic drugs are increased when they are in ionized state. To enhance the solubility of drug, pH of a drug solution is adjusted, but it may be possible that it may lead to instability of a drug substance. To resolve this issue, a water-soluble solvent is added into the solution; as a result, stability of drug increases by reducing the ionization, pH requirement to achieve high solubility, increasing the solubility, and decreasing the activity of water by minimizing the polarity of solvent. For example, 20% propylene glycol is added in chlordiazepoxide injection to enhance the solubility by increasing the stability and ionization of drug. The chemical reactions are catalyzed by pH; the rate of such chemical reaction is monitored by determining the rate of degradation of drug against concentration constant of solvent, temperature, pH, and ionic strength.

Some buffers such as lactate, acetate, phosphate, citrate, and ascorbate buffers are used to minimize the effect of change in pH on drug. Tenfold reaction rate constant is increased by only a change in 1 unit pH. So, before the formulation of a solution in which drug is to be dissolved, it is necessary to develop pH decomposition profile. Data obtained from this profile will help to formulate a solution which is physiologically stable.

1.10.4 Concentration

The solutions having the same drug with different concentration show the same rate of degradation of drug. The ratio of amount of degraded drug and total amount of drug in concentrated solution is less than that of diluted solution.

1.10.5 Moisture

Due to presence of water, microbial growth occurs. Many drugs are degraded due to oxidation, reduction, and hydrolysis. Moisture will promote these chemical reactions; as a result, degraded products are formed.

1.10.6 Water

Water is responsible for hydrolysis of many drugs. Hydrolysis means splitting of substance in the presence of water. Most of drug substances having functional group such as amide and esters undergo degradation. For example, sodium acetate on hydrolysis produces acetic acid and hydroxide. The drugs containing beta-lactam ring undergo fast decomposition reaction than drugs containing ester, imide, and amide groups following first order of reaction. Mostly these types of reactions occur in the presence of divalent metal ions, light, heat, and large concentration of drug [25].

1.11 Conclusion

The main purpose of pharmaceutical analysis is formulation of drug free from any impurities or degraded products to protect human being from any harm. The pharmaceutical formulations must be physically, chemically, microbiologically, and therapeutically stable. The main aim of this review is to use analytical instrumental techniques and kinetic reactions for determining the stability of the drugs. This review highlights the routes of degradation of drugs. Various factors affect the stability of drugs such as oxygen, pH, concentration, temperature, humidity, and moisture.