IMPORTANCE OF DRUG EXCIPIENT COMPATIBILITY STUDIES BY USING OR UTILIZING OR EMPLOYING VARIOUS ANALYTICAL TECHNIQUES – AN OVERVIEWHTML Full Text
IMPORTANCE OF DRUG EXCIPIENT COMPATIBILITY STUDIES BY USING OR UTILIZING OR EMPLOYING VARIOUS ANALYTICAL TECHNIQUES – AN OVERVIEW
Rajesh *, Velimidi Navya and Selva K. Kumar
Department of Pharmaceutical Analysis, Acharya & BM Reddy College of Pharmacy, Soldevanahalli, Hessarghatta Main Road, Bengaluru, Karnataka, India.
ABSTRACT: The interaction/incompatibility of drug excipients is a major concern in formulation generation. Compatibility tests for drug excipients constitute an important step of the production of all dosage forms in the preparation stage. The possible physical and chemical interactions of drugs and excipients can influence chemical, physical, therapeutic properties and the dosage form's stability. The current review involves a fundamental mode of drug degradation, a process of physical, chemical and biopharmaceutical interaction between drugs and excipients. The study of incompatibility is explored in various thermal and nonthermal methods. Once the interaction form is identified, further steps can be taken to enhance drug and dose stability. Current and potential reviews of case studies relating to drug and excipient interactions and their unavoidable incompatibilities have also been studied to deepen greater information about such drug solution scenarios. From the review, we conclude that the subsequent use of the thermal and nonthermal methods provides information for the drug-excipient interaction, which can aid the production of safe dosage forms by selecting an excipient.
Keywords: Drug-excipient compatibility, Incompatibility, Interactions, Nonthermal methods and thermal methods
INTRODUCTION: The complete characterization and explanation of the physicochemical interaction in dosage forms of an API is an important component of this new preparation of pre-formulation development as it is better suited for users' safety, efficacy, and reliability of their product drug. The API is in close connection with the other components (excipients) of the formulation form that is dosed and guarantees the administration, distribution and protection of the active component from the environment.
The physical elements, i.e., the biological properties or chemical degradation of the medication, while the medicines are pharmacologically inert, the physical compounds would likely share a balance of their levels with that of drugs to create equilibrium in the products being allocated medicines with other pharmacologic drugs. It is necessary to maintain the excipients carefully to improve patient compliance and the liberation and bioavailability of the drug, as well as raise the life savings to the highest level concerning the successful treatment of dosage forms facilitating administration.
An API's compatibility checking for excipients and other active ingredients is recognized as one of the compulsory variables and is a leading investigator in drug product science and technology 1, 2.
In the drugs production development model for success, a full understanding of the physicochemical interactions in a medication type is required. The investigation approach to incompatible API research in the earliest stages of the prevention tools considerably developed and methodological results in the beforetime of prediction, assessment and definition of incompatibility of API, to minimize expensive waste in our materials and considerably lower time to obtain appropriate articulation 3.
Incompatibility: If a medication is inactivated by turning it into a less advantageous shape, either because of drug decomposition or waste. If two or more API's and/or excipients are combined and defense, therapeutic efficacy, picture or appeal are both antagonistic and adverse, their objectivity would be considerable if they were diverse 3. Drug compatibility is based on a suspected number of the most suitable excipients that have an important role to play in designing the optimal and reliable dosing scheme concerning the ideal physicochemical properties and solidity 4, 5. Creative Biolabs provides compatibility research in three forms of incompatibility on drug extractors as shown in flow chart 1.
Significance of compatibility of drug excipients
- It is possible to optimize the stability of the dosage type. Any drug-excipient physical or chemical interaction may affect the stability and bioavailability of the drug.
- It helps to prevent issues of surprise. We can understand the potential response before formulating the final dosage form by conducting drug excipient compatibility studies (DECS).
- For IND (investigational new drug) submission, DECS data is critical. Currently, the USFDA has made it mandatory to send DECS data prior to its approval for any upcoming new formulation.
- Determine a number of excipients in the final dosage type that can be used.
- Reduction in dosage type of the associated side effects of the medication due to DECS.
- To solve issues related to multiple excipients being integrated 7, 8.
Flow Chart 1: Incompatibility on Drug Extracts
Excipients: In order to give a different consistency, pharmaceutical excipients are materials that come in the finished dosage formulary, other than pharmacologically active medicines or prodrugs 9, 10.
The role of Excipients:
- To protect, promote or improve the formulation's stability.
- In the case of a potent drug, bulk ups the formulation to help in the formulation of an effective dosage form.
- Develop the acceptance of patients.
- Support to improve active drug bioavailability.
- Improve the overall security and efficacy of the formulation during its use and storage 9, 10.
Process of Decomposition of Drugs: There are invariant features of architectonic drugs that bind with receptors to promote the regulation of metabolism, which are invariable. This shall offer a certain degree of liability in a given sense. This will make them at deterioration (interaction with other materials). It consists of dehydration/hydrolysis, decarboxylation and epimerization/Isomerization, polymerization and other kinds of reactions and polymerization that can be generalized into the thermolytic state. These reactions generally depend upon temperature and can be thermal sensitive. Accelerations by raising the temperature in solid state in various ways (low and high humidity). At a wide range of the pH ranging speeds the hydrolytes can be determined both by exposure to a rising temperature, and by the multiplying pH rates exposure. Generally, in the case of pharmaceutical oxidative degradation would be the outcome. This motive for the output of radicals (Transition metals by initiators such as molecular oxygen or low peroxide levels). The absorption of photons initiates a photolytic reaction by being exposed to various light sources 11, 12, 13, 14.
Popular Degradation Modes are Listed below 11,12,13,14:
Hydrolysis: Function-supporting medications may be tailored to the breaking down of esters or of the lactone. Due to the prevalence of those groups and the abundance of water content of medical agents, it may have been the type of degradation of drugs that is most commonly observed. Water can also act or help microbial production as the interface means.
Oxidation: Oxidative degradation is the first thing that only hydrolysis entails, as a decomposition process. Unlike hydrolysis, the oxidative phase, which consists of either removing the electropositive atom, the electron, the radical electron, the electronegative movement. An addictive movement for an oxidative species might prove complicated. Oxidation responses can catalyze light, heavy metal ions and oxygen resulting in formation of free radicals. Free radicals respond to peroxy radicals by making their own reaction to oxygen; this reacts by producing extra free radicals that, by using an oxidize. Phenols, alcohols, fats and oils, alkaloids are all subject to oxidation by all.
Polymerization: Dimeric and a higher molecular weight can be taken into account by inter-molecular reactions. Ampicillin, amino penicillin, condensed options and dimmers were more, more frequently developed; they are in the trim, essentially polymer degradation. There are examples in Table 1, which provide examples of medicines subject to such modest degradation. Vulnerability of environmental stressors may imply degradation such as heat, humidity, light or drug interactions. Degradation can be encouraged or stimulated by recipients with the desired groups or containing remainders that participate/catalyze in breaking processes may be also facilitated or encouraged. If excipients are also vulnerable to changes, this offers essential possibilities for emerging species involved in processes of division.
Isomerization: Isomerization includes the transition to a chemical's optical or geometric instillation. There may be different pharmacological and toxicology properties of the isomers. In the levo (L) adrenaline form is fifteen to twenty times higher than dextro (D) variety.
Photolysis: Reactions of reduction of a ring modification to polymerized material can be accelerated or catalyzed by being exposed to artificial sunlight or sunlight.
At shorter wavelengths the energy absorption is much bigger and medically absorbed UV light, so it would have been the majority of loss low wavelength light.
Even if chemical replication is stable or even undue exposure to highly generate more and more causative color discoloration is almost always reflected.
TABLE 1: DEGRADATION MODES FOR THERAPEUTIC AGENTS
Mechanism of Interaction between Drug Excipients: The exact mode of conversation with medication items is not clear. However, there are several well-known processes in the literature. Drug excipient contact occurs more frequently than the interaction with excipient and API. Generative contact with drug excipients is either dangerous to treat or can easily be classed as-
- Interactions physically (physical interactions)
- Interaction with chemicals (chemical interactions)
- Interactions of biopharmaceutics (Biopharma-ceutical interactions) 11, 12, 13, 14
Interactions Physically: Physical interactions are much noticed and often difficult to detect in dose form.
TABLE 2: PHYSICAL INTERACTIONS
|Examples of beneficial results
|Examples of Adverse effects
|Complexation: Complexing agent is reversibly bound to drugs to their complex form. Indolen complexes whichlead to a lesser dissolution and lowered a reducing of severe use and medical costare often created. Complexing drugs may also be use to improve the bioavailability of compounds that are poorly soluble in water, which is beneficial
|Cyclodextrins is also commonly used to improve the bioavailability of low solubility drugs for use toavoid witnessing certain pulmonary substances. This enhances bioavailability and increases the drug dissolution rate and grade
Tetracyclines formsanin soluble complex resulting in a slower dissolution and absorption of calcium carbonate
|Solid dispersion: This form of interaction facilitates the bioavailability and dissolution of hydrophobic drugs. Solid dispersion events can also results in restricted drug release
|Some improved dissolution ratesfor pharmaceuticals such as Norfloxacin, piroxicam, ibuprofen and nifedipine were observed. When these drugs were created at solid dispersive levels with polyethylene glycol under various weights of the medical treatment
|Due to the interaction between stearic acid and povidone, strong dispersion product developed in capsule revealed gradual drug dissolution
|Adsorption: Drug adsorption from the excipient could lead to less bioavailability because it is not accessible. Drug adsorption on the excipient surface canhelp increase the surface area of use in the case of dissolution drug that will eventually improve bioavailability
|With kaolin as the adsorbent indomethacin (NSAID)product enhanced its dissolution rate, leading to an increase in bioavailability of drugs
|Cetyl chloride cations are adsorbed to a surface of magnesium stearate which is used as the lubricant in the tablet of the chloride containing tablets. This contributes to a significant decrease in antibacterial activity of the drug
Physical interaction may involve chemical alterations or may not allow materials to preserve their molecular structure in the formation. Physical ties include dissolution shifts, solubility shifts, decreased deposition rate, etc. The incorporation of physical interactions that rely on its completion can be advantageous to, or hinder, the output of an instrument. The following Table 2 is distinct physical interactions.
Interaction with Chemicals (Chemical Interactions): The violent health tools and excipients approach themselves to create unsafe compounds. Chemical interactions typically have a toxic effect on the composition, so avoiding those kinds of interactions is generally necessary.
Interactions of Biopharmaceutics (Bio-pharmaceutical Interactions): These are the behaviors recorded following the use of the medication. The association of medication with body fluid has an effect on the rate of absorption. With all excipients are given along with pharmaceutical active ingredients, several instants of biopharmaceutical interactions express physiologically in a positive way: Detailed note about biopharmaceutical interactions was shown in flow chart- 2.
Flow Chart 2: Biopharmaceutical Interactions
Evaluation Approaches for Compatibility with Medication Excipients: With the objective of reducing or mitigating the unwanted reactions (stability issues) induced by the lack of compatibility, researchers investigated different thermal and unforeseeable analytical methods for early prediction of adequate dosage agents. To date, no popularly decided procedure is available for the assessment of drug compatibility with other substances. However, in the past decade there has emerged a range of research that underscore the use of scientific methods for performance testing on APIs as part of the quest for suitable catastrophe. In possible tests of cold scans they are widely used analytical methods, such as DSC, heat ratings, differential thermo thermal analysis, isothermal calorimetry for the hot stage microscopy as well as other research techniques, such as PXRD (powder x-ray diffraction), optical electron microscopy, HPLC or therapeutic instruments. Relatively new spectroscopic techniques for studying drug moisture or drug and excipient interactions, which may lead to the instability of active tenets, such as solid state magnet resonance spectroscopy and near infrared spectroscopy, have been applied. Very new spectroscopic techniques such as NMR spectroscopy of solid state and close IRS are available in the science of pharmaceutical solid spectroscopy possible applications. Such techniques differ according to their theory, sample machine and thermal stress, the length of the testing necessary, and sample quantity needed, techniques sensitivity to minor change changes, and the need for external or internal requirements. In fact, some of the knowledge theory evaluation methodologies listed had weak predictive outcomes, while some have timely pharmaceutical product development policies did have a larger impact upon pharmaceutical marketers. Therefore, the thermal and nonthermal approach combinations make an efficient means to describe incorrectness in the proper manner 1, 15.
Detailed note about analytical tools for APIs compatibility evaluation was shown in flow chart-3.
Flow chart: 3 Analytical Tools for APIs Compatibility Evaluation:
TABLE 3: ANALYTICAL TOOLS AND APPLICATIONS 1, 16-45
|Isothermal microcalorimetry (IMC)
|Determination of drug excipient compatibility, Stability testing, Identification of polymers
|Hot stage microcalorimetry
|Thermal testing (melting/ boiling points), Compatibility tests, Interactions, Visualization
|Differential scanning Calorimetry (DSC)
|Assessment of the effects of structural change on a molecule stability, Measurement of ultra-light molecular interactions, polymers, General chemical analysis
|Differential thermal Analysis (DTA)
|Determination of pharmaceutical incompatibility, polymeric materials, Qualitative and quantitative identification of minerals, Melting point and fusion heat
|Determine the structure of the material, Determine thermal stability, To study the kinetics of the reaction rate constant
Determine the purity of a mineral, inorganic compound or organicmaterial
|Solid state nuclear magnetic resonance spectroscopy (ssNMR)
|Polymorph identification, Quantitation, Amorphous characterization
|Determining the structure of the material, Determine thermal stability, To study the kinetics of the reaction rate constant, Determine the purity of a mineral, inorganic compound or organic material
|Powder X-ray diffraction (PXRD)
|Identification of unknown crystalline materials like minerals and inorganic compounds, Determination of unknown solids in environmental science, material science and biology
|Scanning electron microscopy (SEM)
|Image morphology of samples, Image compositional and some bonding differences
|High-performance liquid chromatography (HPLC)
|Determine the chemical interaction with API, Environmental chemistry, Structural determination
Qualitative and quantitative analysis
|TLC or High-performance thin layer chromatography (HPTLC)
|Chemical interactions between excipients and drugs, Quantify incompatibilities, Environmental analysis
Analytical Tools for Apis Compatibility Evaluation:
Thermal Analytical Approaches: In compatibility screening study, thermal analysis plays a vital role and is widely used to rapidly determine physicochemical incompatibility. Standard testing compatibility approaches require a couple of sample preparations and extended storage times to produce meaningful results. The thermal methods, however, provide possible benefits over the traditional techniques of isothermal stress testing (IST). The thermal analysis prevents the time and production methods being storable with all the compounds available during an interaction timer and a limited number of experiments are allowed for screening short duration. The outcome found from thermal techniques are direct indications that are probable to be consistent with that excipient, reducing the traditional samples of compatibility to be prepared and thereby saving valuable time 2.
Isothermal Micro-calorimetry (IMC): In the field of solid-state pharmaceuticals, isothermal micro-calorimetry has been shown to be an indispensable technique with its important application on the determination of compatibility. This operates on the theory that within their environment, both chemical and physical processes are followed by exchange of heat. This will make it possible to measure small values of heat produced or absorbed and readily observe the signal of heat flow over the µm range. In addition, without requiring several sample preparations and long storage periods, the micro reaction calorimeter gives meaningful results. During a standard experiment for consistency, the device, the solid or suspension combination of the excipient and the API is transferred to the thermal and the calorimeter habits are regulated, at a continuous temperature, and are subject to control. The basic concept is that the production rate of heat is proportional to the production rates of chemical and/or physical processes sampled.
Excipients and API thermal activity are individually considered and the effectiveness of the assemblage is compared with the structure used on the separation elements. When a significant distinction is analytically established, the excipient will be considered to be theoretically incompatible with the API. Before trying to compare the signal with the rate of degradation, due precaution should be exercised as the signal may involve the amount of different chemicals and physical processes.
The process can, instead, be used as an indication of possible incompatibility. Applying these basic test parameters decreases the amount of samples to be screened using X-ray, HPLC and other time-consuming methods, saving precious effort and time in the process of formulation 16, 17, 18.
Hot Stage Microscopy (HSM): The most popular technique which includes thermal testing and microscopy of all the best features is thermo microscopy or hot stage microscopy (HSM). It is, therefore, a complementary thermal evaluation method useful to visualize the reports of thermal events reported TGA and DSC as well as the versatile method of strong condition showing.
Although isothermal micro-calorimetry and DSC are consider as effective method, some tests confirmed that co-use of HSM aids in establishing incompatibilities properly. HSM allows efficient monitoring of solid condition interactions as a visual thermal analysis technique, such as potential dissolution of one part into another that could be wrongly perceived by DSC as incompatibility. Secondly, one component's deterioration is not obscured by another thermal occurrence.
The visual organization therefore allows for potential distinctions between interactions of the solid state and incompatibilities. When conducting compatibility tests, the necessity of little amounts of samples for visual inspection is of great benefit. HSM is considered a flexible method for DSC and TGA to predict thermal events, as well as for the broadcast interactions of solid-state. The thermological analysis method incorporates the advantage of thermal and microscopic study in order to allow multimedia products and their crystal colors and hydrates to be identified.
The existence of the HSM analysis additionally enhances the benefits and utility of combination studies, whereas previous thermal systems were effective. The visualization of thermal processes on component mixtures could make HSM an effective way of understanding such erroneous DSC explanations.
Visualization may therefore make a difference among solid-state relationships and incompatibilities. One more immense benefit of this approach is that a little amount of sample is required. This approach is therefore united with SEM and DSC for greater component classification possibilities 19-25.
Differential Scanning Calorimetry (DSC): DSC is predominance thermal analyzes approach, which has been heavily used for incompatibility detection of aging chemistry and medicine for more than 50 years. This method compares strictly constituent DSC- curves with curves obtained during this series from 1: 1 physical blends. If the elements are unmatched with each other, the thermal characteristics of the blends (merging point, movement in enthalpy, etc.) can seem to be the number of the elements. The people who use or work will seem to use it; Incompatibility shows an absence, considerable variation in the confusion of components, or the creation of a fresh peak of exo/endothermic and/or changes in enthalpy of the physical mixture response. However, due to potential variations in the mixture geometry, minor changes in the height and width of the peak shape are expected. In terms of short analysis time and low sample consumption, DSC stands to benefit from other traditional methods. It also offers valuable indicators of possible issues, such that at the initial stage of product production an excipient may be rejected. The significance of working relations with an active API can be evaluated detailed where the excipient is required, if the excipient must be specified. The results based on DSC outcomes alone, considering all the merits, can be misleading and need to be carefully interpreted 26-27.
Differential Thermal Analysis (DTA): DTA has, like DSC, been employed to determine inconsistencies in strong states for the previous 5- decades, using DTA. DSC and DTA are normal in some instances and the same thermal actions can be observed. The key interest of such method for its use in determination of pharmaceutical incompatibility was the experimental simplicity, quick estimation and the need for a limited amount of spectrum. Similar to DSC, DTA is often used for calculating both the melting point and the fusion heat. DTA, however, differ in several factors with the DSC, including how the DTA variance of heat is measured, while DSC measures the shift in enterprise; DTA is less powerful in combination with an older technique than DSC; the DSC can be seen as a better version of DTA so DSC has been especially sensitive; however the sample needed in DTA, despite its quantity, four times higher than DSC is of course 16, 28.
Thermo Gravimetric Analysis (TGA): TGA is used both for determining the structure of the material and for determining thermal stability. The loss/gain, i.e. the weight/mass change and rate of such changes can therefore be calculated as a measure of the group heat, atmosphere and time. There may be changes in mass or weight, as a consequence of decomposition, decrease, evaporation, or desorption, though weight decreasing can also be the result of absorption and oxidation. Therefore, the characterization of drugs is simply measured when a change is found in peso caused by chemical or natural interactions. TGA has been able to provide a variety of pieces of information on the components tested, including complex mixture composition, oxidative potential, thermal stability, reactive/corrosive environment effect, lifetime test sample estimate, decomposition characteristics, volatile and humidity content. Bom and team conducted a TGA analysis of multi-walled carbon nanotubes (MWCNT) tempered at 2200-2800 degrees C and stable with annealed graphite has been found. The outcomes have shown defects to favour oxidative degradation at the bottom of the standard nanotubes and along the walls.In recent years, CNTs have proved to be excellent drug carriers. A similar description of the decorated nanoparticle of MWCNT boron carbide was used very recently for the study of samples in various growth stages 29-32.
Solid State nuclear Magnetic Resonance Spectroscopy (ssNMR): In quantitative and qualitative evaluating pharmaceutical solids (APIs and drug formulations), ssNMR has demonstrated substantial abilities, sheds light on chemical relationships and pharmaceutical structure, is highly selective and provides a restricted excipient intervention over other conventional research methods. It has a direct gain in the recognition of consistency in a mixture both crystalline and amorphous components. This technique shows that there are interactions between solid state pharmaceutical excipients by adjusting the chemical shift due to differences in the electron density of the carbon atoms concerned. It is also possible to directly measure the molecular water distribution via nuclear magnetic resonance (NMR) mode in an environment which influences chemicals responses.
While it has many benefits over other spectroscopic techniques, it is important for data collection to be long and complicated in many instances. We should remind you that water for extracts such as starch, lactose and cellulose plays an important role in altering molecular mobility of the chemical accelerators system under conditions which are poorly adsorbed. Atomic resonant (NMR) can directly compute water's molecular mobility and a relation to water supply stability in a mixture.
For the qualitative and quantitative determination of pharmaceutical strengths as the technique of pharmaceutical sciences, ssNMR has shown high encouragement. SsNMR will moreover guide the composite and configuration, resonance allocation, molecular motion analysis as well as the distance metering of the compound. SsNMR is therefore a highly selective technique, which helps you to understand the chemical bonding and the structure of chemical substances. It is a very selective material that does not conflict with the study process. In comparison to PXRD, this approach could help to distinguish the mixture elements of crystalline and amorphous solids. The signs of any loss of coherence between the material and the solid-state excipient can also be tested by manipulating chemical changes. In addition to its benefits over other approaches and alignments, it' longer method of collecting information and also because of the mixed meaning of findings 17, 33, 34.
Vibrational Spectroscopy: The organic compound structure and environment is exposed to Raman, FTIR and the near IR spectroscopy structure and atmosphere. These techniques are not only focused on the solid state behavior and formulation of APIs, but also as a compatibility screening tool because the vibrational changes serve as a sample of potential intermolecular interactions between components. Thus pharmaceutical relation resulting in the formation of dehydration, hydrates, polymorphic shift or crystalline shape to amorphous form and conversion may be easily recognized by these spectroscopic techniques during the processing. Nevertheless, the absence of explanatory peaks will prevent study. Thus, FT-IR helped to choose appropriate excipients for a stable solution. It is the most suited, non-determinative spectroscopic method, DRIFT (Diffuse Reflectance Infrared Fourier Transform Infrared Spectroscopy) and has attracted interest because the materials are not subjected to thermal or mechanical energies during sample preparation, preventing solid state transformation. As an essential method for the application of pharmaceutical applications, vibrational spectroscopy are very important where Fourier Transform Infrared (FT-IR), Raman and Near Infra - red spectroscopy are employed. The methods in this class are adjustable to the chemical formation in the fluid and the surroundings where the vibrations of the bond are evaluated as analysis parameters. Vibration shift will thus help to measure the performance of solid-state characterization by the API, as well as to define the intermolecular interaction between various components to test for potential interaction. This technique can therefore easily recognize any sort of pharmaceutical interactions, including hydrate formation or dehydration, morphological changes, desalting, or exchange between crystalline and amorphous.
It is possible to effectively research the use of this form of vibration in the biomedical field. More recent physical contact was between methionine, essential human amino acids and platine and cisplatin or transplatine, aqueous solution. As shown in a mass spectroscopy, response for these two components was demonstrated, that constructs monofunctional complexes of [PtCl (NH3)2 Met]. The cisplatin attack against methionine was seen; however, for differential features in complement forming as measuring by vibratory species indicates a balance between sulfur and nitrogen binding balance. Thus, nondestructive methods of vibration contribute to improvement in the manufacture, without altering the solid state of the materials being tested, of stable formulations in the evaluation of vibrational cells 36, 37, 38, 39, 40.
Powder X-ray Diffraction (PXRD): It is a direct measure of a material's crystal structure, with a typical output being a plot of intensity vs. the angle of diffraction (2θ). There is a particular set of diffraction peaks in a crystalline material and the absence of crystalline API peaks could lead the material to be amorphous or the loading to be too low for exploring with the selected parameters when investigating a dosage form. In the event of incompatibilities that occur during such processes as wet granulation, compression etc, the study of PXRD is of tremendous help and induces changes in the types and polymorphic API when there is composed withdrawn moisture in the presence 41, 42.
Scanning Electron Microscopy (SEM): The method is useful for these structures and the surface patterns of materials are suitable. A drug additive is not supplied with any chemical structure or thermal activity and requires preparation of the sample along with establishes the stage state. But there are certain possibilities to classify incompatible materials by combining SEM studies with other thermal and spectroscopic techniques like DSC, HSM and FT-IR 1, 24, 43.
High Performance Liquid Chromatography (HPLC): For compatibility check, the chromatographic approach was widely used for comparative analysis through quantitative estimating of pharmaceutical excipient test specimens’ isothermal stress testing (IST). For a fixed time period (approximately three to four weeks), the IST covers the containment of drugs by themselves and medicinal product mixes with or without damp at high temperature to speed up any drug and excipient prescription encoding.
The incompatibility of chemicals is then tested in the stored samples by evaluating the drug content. HPLC findings that display a percentage loss equal to the independently considered medication suggest no association between the excipients and the drug, and vice versa.
In order to further classify the incompatibility materials, advanced analytical techniques such as liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS) were used. HPLC technology is time consuming, despite its optimum applicability. Therefore, with a preliminary study of incompatibility using thermal technologies, the latter could be verified by chromatography in order to ultimately determine the chemical interaction with the API 36, 44, 45.
Thin-layer Chromatography (TLC) or High-Performance Thin-layer Chromatography (HPTLC): This technique is important to quantify incompatibilities and there can be strong evidence of interaction and degradation products. Through this approach, the formation of the degradants or estimation of a potential interaction system is not possible. The occurrence of a degrading material that can be eluted to recognize the degradants or characterize it represents a specific function for each person or individual component other than the TLC plate. In the study of chemical interactions between excipients and drugs based on the drug potency in balanced samples, the TLC/HPTLC approach can therefore be used 1.
CONCLUSION: The interaction/incompatibility of drug-excipients is a major concern in the formulation generation. During pre-formulation testing, selecting the right excipient is of utmost importance. The lack of knowledge of the dynamics of chemical and physical interactions or the unexplained occurrence of residue in single grades can be linked to many stability problems experienced during the manufacturing and post-commercialization times. Many of these issues include low levels of creative groups formed by drug and excipient relationships that create safety concerns or accountability problems.
DS systems, pharmacy excipient behavior can take longer to manufacture and are often expected by stress and pre-formulation tests and drugs contact are often negative. A planning strategy or the practicality of the business growth sector can be challenging as well as undermined. Combining knowledge about medicinal product to face degradation reactions through an analysis of the excipient reactivity and the traces may reduce the prospect of such unwelcome and costly situations. Thermal analytical and spectroscopic methods placed a key role in characterizing interactions in solid state and early detection of drug and excipient compatibility. The knowledge and effective use of these analytical approaches is there in full detail. It has been collected useful data on drug interactions to help make available suitable excipients for saving and effective solid type dosage choices. In a nonthermal analysis process, HPLC and FTIR contain precise proof for structural composition. Hot stage microscopy and SEM have minimal chemical knowledge. When thermal changes are not required, the outcomes of the DSC and the DTA are useful and a further nonthermal cycle is necessary. The fundamental conditions needed for producing secure and highly effective dosage forms understand of medication disagreement forms. In order to achieve successful pharmaceutical formulation, development researchers must recognize four crucial components: Advantages and restrictions of the API, beneficial excipients and compound relations and the technique of processing. Drug excipient relationships and associated incompatibility are often regarded as primary concerns of the formulation manufacturing method.
In other words, the understanding and interpretation of formative excipients is the pharmaceutical base. This may be physical, chemical or physiological / therapeutic interactions. Then such interactions between physiological and physical or chemical. The achievement of such biological process interactions, however, can be useful or harmful. If such beneficial interactive functions are achieved, it is necessary to plan previously in the development phased. In addition, the excipient interaction prediction and the relation with inductions reliability cannot always be predicted.
Therefore, the choice of suitable excipients for patented drug use and the interaction analysis must be of utmost importance during the pre-formulation experiments. In this chapter therefore, a strong idea was explored about the relationships between drug excipients and therapeutic drugs in the pharmaceutical industries along with their future mechanisms of causing such degradation. Current and potential reviews of case studies relating to drug and excipient interactions and their unavoidable incompatibilities have also been studied to deepen greater information about such drug solution scenarios. Therefore, the assessment of interactive capacity can be seen as preliminary measures that help stabilize and sustain the therapeutic role needed. Many analytical techniques have been applied in the pharmaceutical industry to research the chemical or physical conditions of a substance to an excipient. The two methods would adopt the following methods. Finally, we have recorded some legislative effects on drug-excipient relationships.To generate stability in pure patient use, planning experts should equally take into account all of the possible experiences with the drug used and the excipients used.
ACKNOWLEDGEMENT: The Authors would like to sincerely thank Acharya & BM Reddy College of Pharmacy, Bengaluru.
CONFLICTS OF INTEREST: All the authors declared that they have no conflicts of interest.
- Niguram P, Polaka SN, Rathod R, Kalia K and Kate AS: Update on compatibility assessment of empagliflozin with the selected pharmaceutical excipients employed in solid dosage forms by thermal, spectroscopic and chromatographic techniques. Drug Dev Ind Pharm 2020; 46(2): 209-18.
- Kaur R and Sinha VR: Use of thermal and nonthermal techniques for assessing compatibility between mirtazapine and solid lipids. J Pharm Biomed Anal 2018; 161: 144-58.
- Sinko PJ and Singh Y: Martin's physical pharmacy and pharmaceutical sciences: physical chemical and biopharmaceutical principles in the pharmaceutical sciences. Walter Kluer 2011.
- Michele S, Francesco L, Anna Maria F, Chiara S and Elena P: Drug-excipients compatibility studies in proniosomal formulation: A Case Study with resveratrol. J Nanosci. Nanotechnol 2021; 21(5): 2917-21.
- Meira RZC, Biscaia IFB, Nogueira C, Murakami FS, Bernardi LS and Oliveira PR: Solid-state characterization and compatibility studies of penciclovir, lysine hydrochloride and pharmaceutical excipients. Materials (Basel) 2019; 12(19): 3154.
- Dinte E, Bodoki E, Leucuta S and Iuga CA: Compatibility studies between drugs and excipients in the preformulation phase of buccal mucoadhesive systems. Farmacia 2013; 61(4): 703-12.
- Gupta KR, Pounikar AR and Umekar MJ: Drug excipient compatibility testing protocols and charaterization: A Review. Asian J of Chemical Sciences 2019; 6(3): 1-22.
- Bharate SS, Bharate SB and Bajaj AN: Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. Journal of Excipients and Food Chemicals 2016; 1(3): 11-31.
- Rahul P, James B and Amr E: Pharmaceutical excipients and drug metabolism: A mini-review. Int J Mol Sci 2020; 21(21): 8224.
- Sandesh NS, Ajeet MG, PankajSG and Sapna K: Significance of pharmaceutical excipients on solid dosage form development: A Brief Review. Asian J Pharm Res 2016; 6(3): 193-02.
- Gupta KR, Pounikar AR and Umekar MJ: Drug excipient compatibility testing protocols and charaterization: A Review. Asian Journal of Chemical Sciences 2019; 6(3): 1-22.
- Narasimha MS and Repka MA: Excipient stability: A critical aspect in stability of pharmaceuticals. AAPS Pharm Sci Tech 2018; 19: 11.
- Fung MH, DeVault M, Kuwata KT and Suryanarayanan R: Drug-excipient interactions: Effect on molecular mobility and physical stability of ketoconazole-organic acid coamorphous systems. Mol Pharm. 2018; 15(3): 1052-61.
- Tian B, Ding Z, Zong S, Yang J, Wang N, Wang T, Huang X and Hao H: Manipulation of pharmaceutical polymorphic transformation process using excipients. Curr Pharm Des 2020; 26(21): 2553-63.
- Derar MO, Yazan A and Assayed S: Drug-Excipient Interactions: An Overview on Mechanisms and Effects on Drug Stability and Bioavailability. Annals of the Romanian Society for Cell Biology 2021; 25(4): 8402-29.
- Schmitt EA, Peck K, Sun Y and Geoffroy JM: Rapid, practical and predictive excipient compatibility screening using isothermal microcalorimetry. Thermochimica Acta 2001; 380(2): 175-84.
- Prakash N, Surya NP, Rajeshwari R, Kiran K and Abhijeet SK: Update on compatibility assessment of empagliflozin with the selected pharmaceutical excipients employed in solid dosage forms by thermal, spectroscopic and chromatographic techniques, Drug Development and Industrial Pharmacy 2020; 46(2): 209-18.
- Gaisford S: Isothermal microcalorimetry. InAnalytical Techniques in the Pharmaceutical Sciences, Springer, New York 2016; 389-409.
- Chadha R, Arora P, Bhandari S and Bala M: Thermomicroscopy and its pharmaceuticals applications. Current Microscopy Contributions to Advances in Science and Technology 2013; Corpus id: 17064474.
- Harding, Qi S, Hill G, Reading M and Craig DQ: The development of microthermal analysis and photothermal microspectroscopy as novel approaches to drug–excipient compatibility studies. International Journal of Pharmaceutics 2008; 354(1-2): 149-57.
- Kumar A, Singh P and Nanda A: Hot stage microscopy and its applications in pharmaceutical characterization. Appl. Microsc 2020; 50: 12.
- Giovanna B, Mirena S, Vittorio B, Lauretta M, Valeria F, Alessandro G, Chiara M and Amedeo M: Physico-chemical and pharmaceutical characterization of sulindac–proglumide binary system. J Therm Anal Calorim 2019; 136: 2063–70.
- Aminu N, Chan SY and Mumuni MA: Physicochemical compatibility studies of triclosan and flurbiprofen with excipients of pharmaceutical formulation using binary, ternary, and multi-combination approach. Futur J Pharm Sci 2021; 7: 148.
- Meira RZC, Biscaia IFB, Nogueira C, Murakami FS, Bernardi LS and Oliveira PR: Solid-State Characterization and Compatibility Studies of Penciclovir, Lysine Hydrochloride, and Pharmaceutical Excipients. Materials 2019; 12(19): 3154.
- Yang M, Wang P, Suwardie H and Gogos C: Determination of acetaminophen's solubility in poly (ethylene oxide) by rheological, thermal and microscopic methods. International Journal of Pharmaceutics 2011; 403(1-2): 83-89.
- Brusac E, Jelicic ML, Cvetnic M, Amidzic Klaric D, Nigovic B and Mornar A: A comprehensive approach to compatibility testing using chromatographic, thermal and spectroscopic techniques: Evaluation of potential for a monolayer fixed-dose combination of 6-mercaptopurine and folic acid. Pharmaceuticals 2021; 14(3): 274.
- Rojek B and Wesolowski M: DSC supported by factor analysis as a reliable tool for compatibility study in pharmaceutical mixtures. J Therm Anal Calorim 2019; 138: 4531–45.
- Veras KS, Fachel FNS, Pittol V, Garcia KR, Bassani VL, Dos Santos V, Henriques AT, Teixeira HF and Koester LS: Compatibility study of rosmarinic acid with excipients used in pharmaceutical solid dosage forms using thermal and nonthermal techniques. Saudi Pharm J 2019; 27(8): 1138-45.
- Corazzari I, Nistico R, Turci F, Faga MG, Franzoso F, Tabasso S and Magnacca G: Advanced physico-chemical characterization of chitosan by means of TGA coupled on-line with FTIR and GCMS: Thermal degradation and water adsorption capacity. Polymer Degradation and Stability 2015; 112: 1-9.
- Bom D, Andrews R, Jacques D, Anthony J, Chen B, Meier MS and Selegue JP: Thermogravimetric analysis of the oxidation of multiwalled carbon nanotubes: evidence for the role of defect sites in carbon nanotube chemistry. Nano Letters 2002; 2(6): 615-19.
- Tekade RK, Maheshwari R, Soni N and Tekade M: Carbon nanotubes in targeting and delivery of drugs. InNanotechnology-based approaches for targeting and delivery of drugs and genes. Academic Press 2017: 389-26.
- Muthu RN, Rajashabala S and Kannan R: Hexagonal boron nitride (h-BN) nanoparticles decorated multi-walled carbon nanotubes (MWCNT) for hydrogen storage. Renewable Energy 2016; 85: 387-394.
- Mingyue Li, Wei Xu and Yongchao Su: Solid-state NMR spectroscopy in pharmaceutical sciences. TrAC Trends in Analytical Chemistry 2021; 135: 116152.
- Alessandro M, Jinglin Y, Yongchao S and Xueqian K; Solid-state NMR in the field of drug delivery: State of the art and new perspectives. Magnetic Resonance Letters 2021; 1(1): 28-70.
- Kumar V, Shah RP, Malik S and Singh S: Compatibility of atenolol with excipients: LC–MS/TOF characterization of degradation/interaction products, and mechanisms of their formation. J Pharm Biomed 2009; 49(4): 880-88.
- Mutalik S, Naha A, Usha AN, Ranjith AK, Musmade P, Manoj K, Anju P and Prasanna S: Preparation, in-vitro, preclinical and clinical evaluations of once daily sustained release tablets of aceclofenac. Archives of Pharmacal Research 2007; 30(2): 222-34.
- Otsuka Y, Utsunomiya Y, Umeda D, Yonemochi E, Kawano Y and Hanawa T: Effect of polymers and storage relative humidity on amorphous rebamipide and its solid dispersion transformation: Multiple spectra chemometrics of powder X-ray diffraction and near-infrared spectroscopy. Pharmaceuticals 2020; 13(7): 147.
- Jamieson LE and Byrne HJ: Vibrational spectroscopy as a tool for studying drug-cell interaction: Could high throughput vibrational spectroscopic screening improve drug development. Vibrational Spectros 2017; 91: 16-30.
- Volpati D, Aoki PH, Alessio P, Pavinatto FJ, Miranda PB, Constantino CJ and Oliveira ON: Vibrational spectroscopy for probing molecular-level interactions in organic films mimicking biointerfaces. Advances in Colloid and Interface Science 2014; 207: 199-15.
- Paciotti R, Corinti D, De Petris A, Ciavardini A, Piccirillo S, Coletti C, Re N, Maitre P, Bellina B, Barran P and Chiavarino B: Cisplatin and transplatin interaction with methionine: bonding motifs assayed by vibrational spectroscopy in the isolated ionic complexes. Physical Chemistry Chemical Physics 2017; 19(39): 26697-07.
- Jie Shu, Jiali Gu and Huipeng Zhao: Solid-state nuclear magnetic resonance techniques for polymer quantitative investigation. Progress in Chemi 2018, 30(12): 1844-51.
- Perdih F, Zigart N and Casar Z: Crystal Structure and solid-state conformational analysis of active pharmaceutical ingredient venetoclax. Crystals 2021; 11(3): 261.
- Kumar A, Singh P and Nanda A: Hot stage microscopy and its applications in pharmaceutical characterization. Appl. Microsc 2021; 50: 12.
- Shahul Hameed KM, Arun kumar M and Dhanapal CK: Characterization of pure drug and drug-excipient compatibility studies of tadalafil. Int J Med Pharm.Res 2018; 6(2): 88-93.
- Priyanka P, Kajal A, Vandana P, Lata M and Chirag P: Drug-Excipient compatibility studies: First step for dosage form development. The Pharma Innov J 2015; 4(5): 14-20.
How to cite this article:
Rajesh R, Navya V and Kumar SK: Importance of drug excipient compatibility studies by using or utilizing or employing various analytical techniques – an overview. Int J Pharm Sci & Res 2022; 13(9): 3473-85. doi: 10.13040/IJPSR.0975-8232.13(9).3473-85.
All © 2022 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
R. Rajesh *, Velimidi Navya and Selva K. Kumar
Department of Pharmaceutical Analysis, Acharya & BM Reddy College of Pharmacy, Soldevanahalli, Hessarghatta Main Road, Bengaluru, Karnataka, India.
28 September 2021
20 July 2022
10 August 2022
01 September 2022