Advancing Drug Chemical Stability: Unravelling Recent Developments and Regulatory Considerations

Shrikant Mahesh Sharma^1*, Rupali Sharma¹, Pankaj Chandrateya² and Satish Sardana^1
*Correspondence: Shrikant Mahesh Sharma, Department of Pharmaceutical Sciences, Amity Institute of Pharmacy, Amity University Haryana, Manesar, Gurugram -122413, India, Email:

Keywords

Chemical stability • Semisolid dosage forms • Stability guidelines • Regulatory considerations • Analytical techniques • Stabilizing excipients • Drug delivery systems • Nanotechnology • Future perspectives

Introduction

Chemical stability is a fundamental concept in the pharmaceutical industry, comprising the ability of a drug or medicinal product to maintain its chemical composition and properties over time, assuring its safety and efficacy for the duration of its shelf life [1]. International standards established by regulatory bodies, most notably the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) [2], govern the evaluation of chemical stability. The ICH stability guidelines offer a comprehensive framework for evaluating the stability of pharmaceutical products. These guidelines incorporate both chemical and physical aspects of stability and are essential for sustaining uniform and standardized practices among international regulatory agencies. ICH Q1A (R2), which was finalized in 2003, was the most recent known revision of ICH stability guidelines as of the most recent update in September 2021 [3]. It is essential to note, however, that regulatory guidelines undergo periodic updates and revisions to reflect the dynamic nature of pharmaceutical practices and standards. To obtain the most recent information regarding the current version and revision date of ICH stability guidelines, it is suggested that to visit the official ICH website or consult with the regulatory authorities in your region. They can provide the latest information on any revisions or additions to these guidelines.

Stability studies are essential, but present numerous challenges for pharmaceutical manufacturers and regulatory agencies. These challenges incorporate protracted study durations, resource intensiveness and evolving regulatory requirements [3]. Complying with these requirements necessitates significant resources, including personnel, equipment and storage space, which can be prohibitively expensive for smaller pharmaceutical companies. Semisolid dosage forms, such as lotions, ointments and gels, present unique difficulties in stability studies due to their complex formulations, which include multiple excipients and their propensity for phase separation, crystallization or degradation over time [1]. Maintaining the desirable physical and chemical properties of semisolid dosage forms over the course of their shelf life requires specialized knowledge and customized stability testing protocols [1]. Now discussing about the types of stability studies.

Types of stability studies

Chemical stability: This chemical stability refers to the examination of a drug's capacity to maintain its chemical integrity over time. The assessment involves the examination of variations in the chemical composition of the medicine, including degradation, development of impurities and modifications in its chemical structure [3].

Physical stability: This Physical stability refers to study and investigate changes in the physical characteristics of the medication, including factors such as colour, visual appearance and physical state (e.g., solid, liquid or semisolid) [3].

Microbiological stability: This stability focuses on the capacity of a pharmaceutical substance to withstand microbial contamination, therefore guaranteeing its preservation without the presence of detrimental microorganisms during the duration of its storage [2].

Biological stability: The concept of biological stability pertains only to biological products, including vaccinations and biopharmaceuticals. The researchers evaluate the biological activity of the substance and its capacity to sustain its therapeutic effectiveness [4].

Thermal stability: Thermal stability investigations assess the stability of the medicine when exposed to different temperature circumstances, including elevated temperatures that mimic storage in hot geographical regions [5].

Photo stability: Photostability refers to the evaluation of a drug's susceptibility to light and its propensity for undergoing photodegradation upon light exposure [4].

The significance of excipients and their roles in ensuring drug stability

Excipients refer to inert chemicals used into pharmaceutical formulations with the purpose of augmenting the stability, effectiveness, or patient acceptance of the medicine. Several crucial excipients play a significant role in maintaining medication stability.

Preservatives: Preservatives are used into formulations with the purpose of inhibiting microbial development, hence guaranteeing microbiological stability during the storage period [1].

Antioxidants: Antioxidants play a crucial role in mitigating the process of oxidation, which is a prevalent degradation route for several pharmaceutical compounds. This is achieved by the scavenging of free radicals and safeguarding the medicine from oxidative breakdown [6].

Stabilizers: Stabilizers refer to excipients that play a crucial role in improving the stability of biopharmaceuticals, vaccines and other delicate medicines. Their primary function is to safeguard these products from deterioration caused by various variables such as elevated temperatures, humidity and other detrimental conditions [7].

Chelating agents: Chelating agents are substances that have the ability to attach to metal ions and effectively isolate them from participating in chemical degradation events, especially those involving oxidation [6].

Buffering agents: Buffering agents play a crucial role in maintaining the pH of a formulation within a defined range. This function is essential for guaranteeing the chemical stability of pharmaceuticals, since a considerable number of them exhibit sensitivity to pH variations [8].

Disintegrants and binders: Disintegrants and binders play a crucial role in solid dosage forms by ensuring the integrity of tablets or capsules, hence eliminating physical instability problems such tablet disintegration or capping [1].

In essence, within the pharmaceutical domain, stability pertains to the maintenance of a drug's chemical, physical and therapeutic characteristics throughout its lifespan. Different categories of stability studies evaluate distinct facets of drug stability and excipients assume a pivotal function in preserving drug stability via the mitigation of degradation processes, hence assuring the safety and efficacy of the product for patients.

The variables that influence chemical stability are discussed

The factors involved in the formulation process are of utmost importance in assessing the chemical stability of medicinal products. The factors under consideration encompass:

pH: The stability of a medicine may be strongly influenced by the pH of its formulation, since some pharmaceuticals exhibit sensitivity to variations in pH levels. For instance, the presence of acidic or alkaline conditions might facilitate the process of hydrolysis or other chemical processes.

Solvent: The selection of a solvent or vehicle in a formulation has the potential to impact the stability of a medicine. Certain solvents have the potential to expedite the breakdown of drugs, whilst others possess the capacity to improve their stability.

Excipients: The chemical stability of a substance may be significantly influenced by the kind and number of excipients used, including preservatives, stabilizers and antioxidants. Excipients are included into the formulation in order to reduce degradation pathways and preserve the integrity of the medicine.

Temperature: The storage temperature of a medicinal product is of utmost importance. Elevated temperatures have the potential to expedite chemical breakdown mechanisms, whilst reduced temperatures have the capacity to decelerate such processes. Therefore, it is essential to provide suitable storage conditions in order to preserve chemical stability.

Importance of chemical stability in the provision of patient care

The need of chemical stability in medical care is of utmost relevance due to several reasons [9]:

Safety: One important consideration is safety, since pharmaceutical drugs that are unstable have the potential to undergo chemical changes, leading to the creation of contaminants or degradation products. If ingested, these contaminants have the potential to provide safety hazards to those receiving medical treatment.

Efficacy: The efficacy of a medicine may be compromised due to a decline in chemical stability, resulting in a diminished pharmacological potency that hinders its capacity to effectively treat medical disorders. The maintenance of treatment effectiveness relies on the critical factor of ensuring stability.

Consistency: One important factor in the healthcare industry is the constancy of pharmaceutical quality and efficacy, which is crucial for both patients and healthcare practitioners. The maintenance of chemical stability is crucial in ensuring the constant delivery of the anticipated therapeutic benefit in each administered dosage.

Patient confidence: It is vital for patients to possess a sense of assurance about the efficacy of their prescribed treatments. The use of stability testing and adherence to stability guidelines in the healthcare industry fosters confidence in the quality and dependability of healthcare goods.

The concept of stability in several domains

Chemical stability issues cover a wide range of factors throughout the pharmaceutical supply chain, extending beyond patient care [10,11].

Temperature control and monitoring:

• Critical temperature range: The critical temperature range for cold storage pharmaceuticals, such as vaccines and biologics, is often defined as a specified temperature range, commonly set between 2-8 ℃. This range is crucial for preserving the chemical stability and therapeutic efficacy of these pharmaceutical products. Variations outside of this specified range may result in the deterioration and diminished effectiveness.

• Temperature excursions: Temperature excursions may arise during the transportation process, particularly in areas characterized by severe climates or when goods are transported over international borders. These are occurrences in which the temperature deviates briefly from the prescribed range. Even brief excursions might have an effect on the stability of drugs.

• Monitoring systems: In order to mitigate temperature-related difficulties, certain monitoring systems, including temperature data loggers and real-time monitoring devices, are used to consistently monitor and document temperature conditions throughout the transportation process. The provided data facilitates the fast identification and response to temperature excursions.

Cold chain logistics:

• Refrigeration units: Refrigeration units are essential for the transportation and storage of pharmaceuticals that need cold storage conditions. The aforementioned trucks are outfitted with refrigeration systems that possess the capability to sustain the necessary temperature range. The adequate maintenance and calibration of these systems are of utmost importance.

• Cold chain integrity: The preservation of cold chain integrity involves many steps, which span manufacture, distribution and last-mile delivery. Every point of transition presents a potential hazard of temperature fluctuation. Ensuring the integrity of the cold chain is important for mitigating stability concerns, necessitating meticulous planning and effective coordination.

• Backup power: The provision of backup power is of utmost importance for refrigeration systems, since it ensures uninterrupted power supply. Backup power sources, such as generators or battery backup systems, are often used to guarantee the maintenance of temperature control in the event of power disruptions throughout the process of transportation.

Packaging and insulation:

• Specialized packaging: The transportation and storage of cold storage medications need the use of specialist packaging that offers thermal insulation and safeguards against temperature variations. Common components of such packing include insulated containers, cold packs and thermal blankets.

• Temperature uniformity: The maintenance of temperature consistency inside the packaging is of utmost importance in order to mitigate the occurrence of hotspots or cold areas that may potentially compromise the stability of drugs. Adequately engineered packaging ensures a uniform temperature distribution throughout its contents.

Supply chain complexity:

• Global distribution: When it comes to foreign exports, pharmaceutical items have the potential to traverse diverse climates and geographies. The preservation of cold chain integrity may be complicated because to variations in regulations, handling techniques and infrastructure levels.

• Handovers and transitions: Handovers and transitions occur at many stages of the supply chain, including the transfer of items from the producer to the distributor and subsequently to the pharmacy. If not properly handled, these handovers have the potential to cause temperature changes.

Response to temperature excursions:

• Protocols and trainings: Pharmaceutical businesses and logistics suppliers must to establish clearly defined methods to effectively address instances of temperature excursions. The aforementioned guidelines delineate the appropriate course of action to be undertaken in the event that goods are subjected to environmental circumstances that fall beyond the prescribed range of recommendations.

• Stability assessment: The evaluation of stability is crucial in determining the potential impact of a temperature excursion on the chemical integrity and therapeutic efficacy of a medication. This process may include conducting tests and doing analyses.

Regulatory compliance refers to the adherence to laws, regulations and guidelines set out by governing bodies in a certain industry:

• Stringent regulations: Regulatory bodies impose rigorous mandates on the maintenance of the cold chain and the preservation of medicine stability throughout transit. Failure to comply with regulations may lead to various consequences, such as regulatory actions, product recalls or diminished product effectiveness.

Under conclusion, the task of maintaining the chemical stability of pharmaceuticals stored under cold conditions during transit is a multifaceted undertaking. The process entails precise regulation and surveillance of temperature, dedicated facilities, suitable packing methods and a resilient system for transporting goods under controlled temperature conditions. The collaboration between pharmaceutical firms and logistics providers is crucial in effectively addressing the issues associated with the transportation and storage of pharmaceuticals, especially those that need cold storage, to guarantee the safety and efficacy of these drugs for patients.

Importance of transport validation

Transport validation, sometimes referred to as shipment validation or distribution validation, encompasses the evaluation and verification of the integrity, quality and efficacy of pharmaceutical goods or sensitive materials throughout their transit and distribution phases. Transport validation plays a crucial role within the pharmaceutical and healthcare sector due to a multitude of reasons:

• Compliance with regulatory requirements: The maintenance of regulatory compliance is essential for pharmaceutical companies to meet the requirements set by regulatory authorities, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). These authorities mandate that pharmaceutical companies provide evidence to substantiate the stability and efficacy of their products throughout the entire distribution process. Transport validation is a process that assures adherence to the specified requirements [12].

• Patient safety: The primary objective of transport validation is to guarantee the administration of safe and efficacious pharmaceuticals to patients, hence prioritizing patient safety. In the absence of adequate validation, items that are subjected to adverse circumstances during transit may see a decline in their chemical stability, hence giving rise to possible safety issues [12].

• Product efficacy: The efficacy of pharmaceutical products pertains to their ability to effectively cure or prevent certain medical problems. If the vaccines are compromised during the process of shipping, their effectiveness may be substantially diminished, hence leaving them ineffectual in the treatment of patients [13].

• Preservation of product quality: The preservation of product quality is ensured by the process of transport validation. This validation procedure serves to preserve the quality of pharmaceutical goods. Degradation or damage to products may occur as a result of temperature excursions, exposure to humidity, or physical shocks experienced during travel, hence impacting the overall quality of the product [10].

• Cost savings: Implementing measures to maintain product stability throughout transit may lead to cost savings for pharmaceutical businesses. This is due to the potential reduction in expenses associated with product recalls, which can have significant financial implications and negatively impact the company's image [14].

• Supply chain efficiency: The optimization of transit validation has a significant role in enhancing the efficiency of the pharmaceutical supply chain. By implementing strategies to mitigate the potential for product deterioration or damage during transportation, the need for supplementary quality control procedures and retesting upon delivery is reduced [15].

The validation process of transportation

The process of transport validation encompasses a series of essential steps [15,16]:

• Identification of critical factors: The objective is to ascertain the key factors that have the potential to impact the product throughout the transportation process. These variables include temperature, humidity, shock and light exposure.

• Simulation testing: Simulation testing involves the execution of controlled experiments or simulations that accurately recreate the circumstances that goods are expected to face throughout transit. Temperature-controlled chambers have the capability to replicate temperature fluctuations, as an example.

• Monitoring and data collection: The process of monitoring and data collection involves the use of data loggers and monitoring devices to systematically record and document the various environmental conditions experienced throughout the transportation process. Gather data pertaining to temperature, humidity, shock and other pertinent characteristics.

• Data analysis: The obtained data will be analysed in order to evaluate whether the product maintained its adherence to permissible limits during the transportation process. Assess any deviations from the prescribed conditions.

• Documentation: This documentation process aims to comprehensively document the process of transport validation, including the protocols used, the obtained findings and any subsequent corrective measures implemented. It is important to maintain thorough and complete records in order to ensure compliance with regulatory requirements.

• Continuous improvement: The validation of transport is a continuous and continuing activity. It is essential for companies to engage in a constant process of reviewing and updating their validation standards in response to evolving transportation methods, goods and laws.

In summary, the validation of transportation has significant importance within the pharmaceutical sector as it serves to guarantee the secure and efficient distribution of pharmaceuticals to those in need. The adherence to rules aids in ensuring compliance, safeguarding patient safety, maintaining the effectiveness and quality of products and enhancing efficiency and cost-effectiveness within the supply chain.

Stability during the manufacturing

The maintenance of stability throughout the manufacturing process is a crucial element in pharmaceutical production, as it guarantees the uniform quality, safety and effectiveness of pharmaceutical products. The process entails the regulation and surveillance of many parameters in order to mitigate deterioration or changes in the chemical composition of the pharmaceutical substance or product during the production phases.

• Ensuring batch-to-batch uniformity: The maintenance of batch-to-batch uniformity has paramount importance in the field of pharmaceutical manufacture. Stability tests are performed in order to validate the consistent quality of each batch of a product, including its chemical composition, potency and purity. This practice guarantees that the ultimate outcome conforms to predetermined standards and complies with regulatory obligations [1].

• Process control: The use of stringent control measures in manufacturing processes is necessary in order to mitigate any potential deviations that may have adverse effects on the stability of the final product. Continuous monitoring is conducted to guarantee that many parameters, including temperature, humidity, mixing durations and equipment calibration, are maintained within predetermined limits [1].

• Evaluation of raw materials: Stability evaluations include the examination of the raw materials used in the production of pharmaceuticals. It is important for manufacturers to maintain the stability and adherence to quality requirements of raw materials in order to prevent the introduction of instability into the ultimate product. This includes the performance of stability studies on excipients and Active Pharmaceutical Ingredients (APIs) [13].

• Intermediate product stability: The stability of intermediate products throughout various phases of manufacture, such as granulation or tablet compression, plays a critical role in ensuring the overall stability of the final product. Stability studies conducted throughout these phases serve the purpose of identifying and addressing stability concerns prior to the formulation of the final product. The maintenance of quality features throughout the process is contingent upon the stability of the intermediate product [10].

• Shelf-Life determination: The estimation of a product's shelf life is influenced by stability tests conducted throughout the production process. In order to determine a suitable expiry date, manufacturers must possess a comprehensive understanding of the product's temporal stability. The provision of this information is of utmost importance in ensuring adherence to regulatory standards and safeguarding the well- being of patients [14].

• Quality control testing: The quality control testing techniques are informed by stability data collected throughout the production process. Manufacturers determine criteria for crucial quality aspects by relying on stability studies. The aforementioned requirements provide guidance for the testing techniques and criteria for accepting the product [14].

• Compliance with regulations: In accordance with regulatory guidelines pharmaceutical businesses are obligated to comply with Good Manufacturing Practices (GMP) as mandated by regulatory bodies, such as the United States Food and Drug Administration (FDA). These GMP standards cover the implementation of stability testing protocols throughout the manufacturing process. Ensuring adherence to these laws is crucial in guaranteeing the safety and effectiveness of the product [15].

• Batch release: The importance of stability data in determining batch release choices. The release of a batch for distribution is contingent upon the confirmation of its adherence to predefined quality and stability requirements via stability testing. The establishment of these criteria is informed by regulatory rules and stability data [15].

• Stability-indicating methods: Stability-indicating procedures are often used by manufacturers in the production process to identify and measure degradation products or contaminants that may have an effect on the stability of the product. These methodologies aid in guaranteeing the discharge of just high-calibre and reliable items [16].

• Quality by Design (QbD): The stability evaluations are in accordance with the principles of Quality by Design (QbD), which is a methodical approach to the development and production of pharmaceuticals. Quality by Design (QbD) places significant emphasis on the criticality of comprehending and managing the factors that have an influence on the stability of a product throughout its production journey [17].

In summary, ensuring stability throughout the manufacturing process is crucial to ensure the consistent production of pharmaceutical goods that adhere to set quality standards. The process includes the surveillance of essential production parameters, evaluation of raw materials and intermediate stages, determination of product shelf life, adherence to regulatory requirements and verification of batch release via the use of stability data. The use of a rigorous strategy aids in the preservation of product stability, therefore guaranteeing the safety of patients and the efficiency of therapeutic interventions. In context of this paper, the scope mostly pertains to the pivotal element of chemical stability within the pharmaceutical sector, specifically concentrating on semisolid dosage forms. The primary focus of this study is the investigation of chemical stability, specifically analysing the impact of different elements and practices on the overall integrity and quality of pharmaceutical goods. Although stability studies include many dosage forms and products, our primary focus is on semisolid formulations.

Factors affecting chemical stability [18-21]:

Environmental factors: The chemical stability of pharmaceutical compounds is significantly influenced by environmental variables. These variables comprise a range of external conditions that have the potential to impact the composition and integrity of pharmaceuticals, particularly in semisolid dosage forms. In this analysis, we explore the four primary environmental factors that have an influence on the stability of chemicals.

• Temperature: The influence of temperature on chemical stability is well recognized as a crucial environmental component. The term "temperature" pertains to the level of thermal energy present in the immediate surroundings, indicating the degree of hotness or coldness. Temperature changes have the ability to induce chemical reactions inside pharmaceutical goods, which may result in the breakdown or modification of the active components. One illustration of this phenomenon is that elevated temperatures may expedite chemical reactions, but very low temperatures can trigger crystallization or phase separation in semisolid pharmaceutical formulations [18].

• Humidity: Humidity refers to the quantity of moisture or water vapour present in the surrounding atmosphere. Elevated levels of humidity have the potential to induce moisture absorption in pharmaceutical goods, hence exerting an impact on their overall stability. Moisture inside semisolid dosage forms has the potential to facilitate the proliferation of microorganisms, induce hydrolysis reactions, or induce physical alterations such as softening or hardening of the formulation. On the other hand, decreased humidity levels might lead to desiccation, resulting in alterations in the consistency of the formulation [19].

• Exposure of light: The phenomenon of light exposure entails the activation of photochemical reactions in pharmaceutical goods, primarily induced by Ultraviolet (UV) and visible light. Light-sensitive chemicals, which are often included in semisolid formulations, have the potential to undergo degradation upon exposure to light. These factors may result in diminished efficacy, alterations in pigmentation, or the generation of contaminants. The use of suitable packaging, such as containers that are opaque in nature, is of utmost importance in safeguarding semisolid items from deterioration caused by exposure to light [20].

• Oxygen and moisture sensitivity: The presence of oxygen and moisture has been well recognized as catalysts for chemical processes, particularly when sensitive medicinal molecules are involved. The presence of oxygen has the potential to begin oxidation events, which may result in the deterioration of Active Pharmaceutical Ingredients (APIs) in semisolid dosage forms. The presence of moisture has the potential to enhance hydrolysis processes by promoting the cleavage of chemical bonds within the formulation. Pharmaceutical makers often use packaging that is both air-tight and moisture-resistant in order to address these sensitivities [21].

The comprehension and regulation of these environmental conditions are of utmost importance in guaranteeing the chemical stability of semisolid pharmaceutical products. Stability testing and packaging considerations are integral aspects of pharmaceutical development that play a crucial role in ensuring the preservation of product quality and effectiveness. Pharmaceutical development can optimize the chemical stability of semisolid dosage forms and uphold the safety and efficacy of their medications for patients by considering and managing environmental conditions throughout the stages of formulation development, manufacture and storage.

Chemical interactions: Chemical interactions have a crucial role in determining the chemical stability of pharmaceutical drugs, particularly those in semisolid dosage forms. These interactions have the potential to result in a range of chemical breakdown processes. In this discourse, we will embark upon an examination of the four fundamental chemical interactions [18-24].

• Hydrolysis: Hydrolysis is a chemical process characterized by the cleavage of chemical bonds within a pharmaceutical formulation by the action of water molecules. The aforementioned procedure has the potential to result in the deterioration of Active Pharmaceutical Ingredients (APIs) and other constituents inside semisolid dosage forms. The process of hydrolysis poses significant challenges for pharmaceutical compounds that have ester or amide linkages, since these chemical bonds are particularly prone to breakage when exposed to water.

Example: The process of hydrolysis may occur in aspirin (acetylsalicylic acid), resulting in the formation of salicylic acid and acetic acid upon exposure to moisture [22].

• Oxidation: Oxidation is a prevalent chemical process characterized by the loss of electrons from molecules. Oxidative reactions pose a considerable problem within the pharmaceutical industry due to their potential to induce deterioration of Active Pharmaceutical Ingredients (APIs) and other constituent components. The initiation of oxidation processes may be facilitated by the presence of oxygen, particularly when catalysts or trace metals are also present. The use of antioxidants in formulations is often employed as a strategy to alleviate this potential hazard.

Example: Ascorbic acid (vitamin C) oxidation in vitamin formulations. Ascorbic acid may degrade when exposed to oxygen, losing some of its effectiveness and potency [20].

• Photodegradation: When pharmaceutical items are exposed to light, especially Ultraviolet (UV) and visible light, photodegradation can place. Light-sensitive substances are susceptible to photochemical processes that might result in deterioration. Impurities may arise, the potency may be diminished, or the colour may alter as a consequence. The use of appropriate packaging, such as opaque containers, may prevent photodegradation.

Example: Tetracycline drugs, including doxycycline, are prone to undergoing photodegradation. The degradation of tetracyclines may occur when they are exposed to light, particularly Ultraviolet (UV) radiation, resulting in diminished efficacy [23].

• Polymerization: Polymerization is a chemical process in which the combination of tiny molecules results in the formation of bigger molecules, referred to as polymers. In the field of pharmaceuticals, such phenomena may manifest in semisolid formulations, resulting in alterations in both the consistency and texture of the product. The solubility and bioavailability of the medication may also be influenced by polymerization.

Example: Certain semisolid dosage forms, such as ointments, have the potential to undergo polymerization of their base constituents. One example is the use of white petrolatum, a frequently employed substrate in ointments, which has the propensity to undergo polymerization as time progresses, so leading to alterations in both texture and consistency [24].

Understanding these chemical interactions is essential for researchers who then may take the necessary precautions to minimize their effects during formulation development, production and storage. This entails choosing appropriate excipients, using appropriate packing materials and doing stability tests to gauge the likelihood of certain interactions developing over time.

Effect of pH and buffering agents: The maintenance of chemical stability of pharmaceutical products, especially those in semisolid dosage forms, is heavily reliant on the presence of pH and buffering agents. The solubility, stability and efficiency of Active Pharmaceutical Ingredients (APIs) may be greatly affected by the pH of a formulation. Buffering agents are used for the purpose of regulating and sustaining the pH within a designated range. The following are some significant and illustrative examples:

• Impact of pH: The stability of several active pharmaceutical ingredients (APIs) is influenced by pH. For instance, there exist distinct pH ranges within which APIs exhibit optimal stability. The pH-dependence of insulin, a peptide hormone used in the management of diabetes, exemplifies its stability. Insulin exhibits stability at acidic pH conditions and its formulations are carefully tweaked to preserve stability within a slightly acidic pH range [25].

• Impact of buffer: Buffering agents, such as citric acid and sodium citrate, are often used in oral and topical medications to maintain a stable pH level. They assist in the regulation of the pH levels in formulations to ensure they remain within the correct range. Citric acid-sodium citrate buffer systems are often used in cough syrups to maintain a mildly acidic pH, so guaranteeing stability and enhancing palatability. Buffering chemicals play a crucial role in the field of pharmaceuticals by effectively mitigating significant fluctuations in pH. Such fluctuations, if left uncontrolled, might result in the destruction or modified solubility of Active Pharmaceutical Ingredients (APIs). The selection process for these components is conducted with meticulous attention to the formulation's unique requirements and the drug substance's stability [26].

Overall, the maintenance of appropriate pH levels and the use of buffering agents are essential considerations in pharmaceutical stability, as they play a crucial role in preserving the active ingredient's stability by ensuring that the formulation stays within the correct pH range. Ensuring accurate pH control and careful selection of suitable buffering agents are crucial factors to be taken into account throughout the process of formulation creation, as they play a pivotal role in preserving the quality and effectiveness of the product.

Impact of packaging materials: The use of packing materials has significant significance in the field of pharmaceuticals, especially in relation to semisolid dosage forms. This is due to their crucial role as the principal protective barrier, safeguarding the product from external elements that have the potential to compromise its stability. The use of appropriate packaging measures has the potential to effectively mitigate the risks associated with contamination, exposure to environmental elements and the deterioration of pharmaceutical products [27-30]. The following are important factors to take into account:

• Protection from environmental factors: One example of protection against environmental factors is the use of aluminium tubes for the purpose of packing ointments. The aforementioned tubes exhibit impermeability to moisture, gases and light, so establishing a commendable safeguard against environmental elements that may potentially undermine the stability of semisolid pharmaceutical formulations.

• Light blocking properties: The light-blocking properties of amber glass containers make them an often-used solution for the storage of medications that are sensitive to light. The aforementioned containers serve the purpose of obstructing Ultraviolet (UV) and visible light, hence impeding the process of photodegradation of the product. An example of the use of amber glass bottles is seen in the packaging of certain vitamin solutions.

• Assurance of sealing integrity: For instance, blister packaging, characterized by the fusion of a plastic sheet to a backing board, serves to guarantee the preservation and safeguarding of individual dose units. The use of this particular style of packaging is prevalent in the context of tablets and capsules, since it effectively preserves the integrity and durability of these solid pharmaceutical dosage forms.

• Tamper-evident features: For instance, several Over-The-Counter (OTC) medicinal products, including lotions and ointments, are equipped with tamper-evident seals as a protective measure. These seals serve as tangible proof of tampering, so improving product safety and ensuring stability for customers.

• Moisture resistance: One use of moisture resistance in the pharmaceutical industry is the inclusion of desiccant packets or sachets inside the packaging of moisture- sensitive drugs. The purpose of these packets is to absorb any moisture that may infiltrate the packing, hence maintaining the stability of the product. Tablets or capsules are often used in packaging applications.

In summary, packing materials are of utmost importance in preserving the chemical stability of pharmaceutical medicines, particularly those in semisolid dosage forms. The appropriate choice of packing materials, taking into account the unique requirements of the product, including safeguarding against environmental elements, light exposure, moisture infiltration and tampering, is crucial in guaranteeing the stability and safety of the product.

Analytical techniques for assessing chemical stability

Analytical techniques play a crucial role in evaluating the chemical stability of pharmaceutical products, including semisolid dosage forms. The aforementioned techniques provide both quantitative and qualitative data pertaining to the composition, degradation and temporal alterations of medicinal substances. This paper provides a comprehensive description of many essential analytical procedures used in stability testing.

• High-Performance Liquid Chromatography (HPLC): The flexible analytical method known as High-Performance Liquid Chromatography (HPLC) is used in the pharmaceutical field to separate, identify and quantify specific components within a given pharmaceutical formulation. The monitoring of Active Pharmaceutical Ingredient (API) deterioration and impurity formation is a commonly used practice in stability testing. High-Performance Liquid Chromatography (HPLC) operates on the fundamental premise of separating chemicals by their interaction with a stationary phase present in a chromatographic column, followed by their subsequent elution.

Example: In the context of stability testing, High Performance Liquid Chromatography (HPLC) may be used as a means to evaluate the degradation of an Active Pharmaceutical Ingredient (API) inside a semisolid dosage form for a specified duration. Through the examination of chromatograms acquired at various time intervals, it becomes feasible to identify the emergence of degradation products and measure their quantities, so enabling a thorough evaluation of chemical stability [31].

• Fourier-Transform Infrared Spectroscopy (FTIR): Fourier-Transform Infrared Spectroscopy (FTIR) is a non-invasive analytical technique used for the investigation of molecular vibrational modes. Fourier Transform Infrared Spectroscopy (FTIR) is a powerful analytical technique that enables the identification of functional groups and the detection of changes in the chemical composition of medicines during stability testing. The process involves quantifying the extent to which molecules absorb infrared radiation.

Example: FTIR spectroscopy may be used for stability testing purposes to effectively track changes in the chemical composition of a semisolid formulation, namely the degradation of ester bonds resulting from hydrolysis. Chemical modifications may be discovered and measured by means of comparing Fourier Transform Infrared (FTIR) spectra obtained from samples collected at various time intervals [32].

• Differential Scanning Calorimetry (DSC): Differential Scanning Calorimetry (DSC) is a thermal analysis method used for quantifying the heat flow linked to thermal changes occurring in medicinal substances. This technique is used in stability testing for the purpose of identifying changes in melting points, crystallinity and thermal stability.

Example: Differential Scanning Calorimetry (DSC) has the capability to evaluate the influence of temperature and storage conditions on the melting characteristics of a substance in a semi-solid state. Through the use of regulated heating and cooling cycles, Differential Scanning Calorimetry (DSC) has the capability to detect alterations in the melting points or the occurrence of novel thermal events in samples. These observations serve as indicators for potential modifications in the stability of the formulation [33].

• Mass Spectrometry (MS): Mass Spectrometry (MS) is a widely used analytical method utilized for the purpose of identifying and quantifying the molecular composition of medicinal substances. The identification and characterization of degradation products in stability testing has significant value. Mass Spectrometry (MS) is a scientific technique that includes the process of ionizing molecules and then determining their ratios of mass to charge.

Example: Mass Spectrometry (MS) may be used to detect and measure distinct degradation products that may arise in semi-solid dosage forms during stability investigations. Through the analysis of mass spectra, Mass Spectrometry (MS) has the capability to accurately determine the specific mass and structure of degradation products, hence enabling precise characterisation [34].

• Other analytical techniques: In addition to the aforementioned methodologies, stability testing may include a range of supplementary analytical procedures, contingent upon the particular requirements of the formulation and the stability investigation. The methods used in this context may include UV-visible spectroscopy, Nuclear Magnetic Resonance (NMR) spectroscopy, Gas Chromatography (GC) and other methodologies specifically adapted to suit the qualities and needs of the pharmaceutical product.

Example: UV-visible spectroscopy is a viable technique for monitoring changes in the absorbance spectra of a semisolid substance, which might provide insights into probable deterioration or modifications in colour. Nuclear Magnetic Resonance (NMR) spectroscopy has the capability to provide comprehensive insights into the structural characteristics of molecules as well as their interactions.

Conclusion

The pharmaceutical industry sets great importance on chemical stability due to its direct influence on the safety and efficacy of therapeutic products. Pharmaceutical items can experience chemical alterations over time, which might render them inefficient or potentially dangerous for patients. Thus, it is crucial to guarantee the stability of these items. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) provides extensive standards for evaluating stability. The guidelines provide an overview of different categories of stability studies that must be carried out to evaluate the stability of pharmaceutical products. The research encompass rapid stability tests, long-term stability studies, and stress testing, among other types of studies. Pharmaceutical companies can assure the stability of their products throughout their shelf life by complying to these standards.

Excipients, the inert components used in pharmaceutical formulations, have a vital function in preserving medication stability. Excipients can impact the chemical stability of a medication by interacting with the Active Pharmaceutical Ingredient (API) and changing its degradation or stability. Hence, it is crucial to meticulously choose and assess excipients to guarantee that they do not jeopardize the stability of the medication. Chemical stability is crucial not only in medical care but also in other areas. Additionally, it includes the control of temperature, logistics related to the cold chain, packaging, and the complex structure of the supply chain. Ensuring temperature control is of utmost importance in preserving the stability of pharmaceutical items, since specific medications may deteriorate or lose their efficacy when subjected to severe temperatures. Cold chain logistics are crucial for maintaining the stability of temperature-sensitive products during transportation and storage in the supply chain.

Furthermore, packaging is crucial in preserving chemical stability. Appropriate packaging is essential for keeping pharmaceutical products against detrimental environmental influences such light, moisture, and oxygen, which can lead to the deterioration of the drug. Furthermore, it is essential for packaging materials to be suitable for the drug formulation to avoid any chemical reactions that might compromise stability. The complex nature of the pharmaceutical supply chain underscores the imperative of adhering to stability requirements. Pharmaceutical products sometimes move through many intermediaries and experience different transportation and storage conditions before they are finally delivered to the end-user. Complying with stability requirements guarantees that the quality and dependability of healthcare products are upheld throughout the intricate supply chain.

Chemical stability is crucial in the pharmaceutical sector since it ensures the long-term safety and effectiveness of therapeutic medicines. ICH offers a thorough framework for assessing stability. The excipients and their interactions with the Active Pharmaceutical Ingredient (API) are crucial in preserving the stability of the medicine. Chemical stability is crucial not just for patient care but also for temperature control, cold chain logistics, packaging, and the complexity of the supply chain. Compliance with stability requirements is essential for ensuring the quality and efficacy of the Pharmaceutical Products.

Acknowledgement

None.

Conflict of Interest

None.

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