INTRODUCTION:

Drug-excipient compatibility is essential in pharmaceutical development to ensure safety and effectiveness. During pre-formulation, evaluating drug-excipient compatibility helps select suitable excipients and maintain formulation stability. Incompatibilities can arise from factors like moisture absorption, pH changes, and exposure to light or heat. Key incompatibility reactions include the Maillard reaction between reducing sugars and primary amines, and oxidation-related issues in excipients like povidone.

Analytical methods such as FTIR, DSC, XRD, and TGA are crucial for assessing compatibility. Fourier Transform Infrared Spectroscopy (FTIR): Identifies incompatibility through changes in absorption bands, indicating shifts in functional groups or the formation of new interactions, such as hydrogen bonding. Differential Scanning Calorimetry (DSC): Monitors heat changes to detect phase transitions or chemical reactions. Incompatibilities are shown by shifts in melting points or new thermal events. X-Ray Diffraction (XRD): Analyses crystalline structures to reveal changes in crystallinity or polymorphic forms due to interactions with excipients. Changes in peak patterns indicate potential incompatibilities.

These techniques help in selecting appropriate excipients to ensure the stability and efficacy of pharmaceutical formulations. The analysis considered the Raman spectrum's lack of vibration mode and the XRD pattern's loss of the calcite reflection. Hydroxyapatite (HA) particle thermogravimetric studies TGA were performed with both reagents at a molar ratio of 0.6. The XRD, TEM, FTIR, XPS, Zetametry, BET, and SQUID magnetometry techniques were used to characterize the samples of ferrite-based magnetic nanoparticles. It the compatibility and physical interactions within EMA/NBR blends using FTIR and DSC.^1,2,3 Study employs DSC, TG, and FTIR to assess API-excipient compatibility, using PCA to resolve overlapping spectra in binary mixtures. In the quest to evaluate API-excipient compatibility, this study utilizes common analytical techniques. When Principal Component Analysis (PCA) reveals distinct clusters in data matrices, it confirms compatibility, whereas the absence of such clusters indicates incompatibility.In FTIR analysis, samples are exposed to infrared radiation, causing specific absorption or transmission of energy based on atomic vibrations. The resulting FTIR spectrum provides information about molecular vibrations in the sample. The methodology involves explaining how to read and interpret FTIR spectra of organic materials, focusing on chemical bonds and structures.^4,5its original structure despite adsorption on AO. The presence of lactose and pimozide in the finished formulationmay be verified based on the distinctive bands that show the presence of calcium phosphate.⁶

RELATED WORK:

XRD analysis would confirm the production of pure aragonite nanoparticles with characteristic diffraction peaks. FTIR analysis confirmed the chemical composition and functional groups in the synthesized nanoparticles. DSC analysis revealed the thermal behaviour and reactivity of the nanoparticles. XRD analysis provided information about the crystal structure and size of the nanoparticles. TGA-DTA analysis FT showed the thermal stability and decomposition characteristics of the nanoparticles. The FTIR confirmed hydrogen bonding between the drug and carriers. DSC indicated partial amorphous form conversion. XRD demonstrated a comparatively higher amorphous transformation in ESDs.^7,8,9

DSC analysis of Effervescence Assisted Solid Dispersion (EASD) indicated changes in melting points, peak features, and crystallinity, suggesting the presence of amorphous forms and possible decomposition in the case of cefuroxime axetil. XRD results showed that the optimized Duloxetine HCl solid dispersion formulation maintained a crystalline form with improved drug release FTIR spectra of all formulations were analysed using a Shimadzu Prestige-21 spectrometer with KBr disks, covering the range of 4000-400 cm^-1 at a resolution of 2 cm^-1. FTIR showed no substantial interaction between the components. DSC confirmed the amorphous nature of the solid dispersion.^10,11,12

The study analysed ritonavir solid dispersion using DSC scans, FT-IR analysis, and X-ray diffraction. Results showed a monotectic system with unchanged carrier melting point, with ultrafine crystals in a polymer matrix. Crystalline peaks indicated amorphous transformation. Suitability may be found between four clusters, the first of which contains API, the second of which is a group mixture at a ratio of 7:3, the third of which is a group mixture at a ratio of 3:7 excipients, the combination of DSC and TGA techniques with modern statistical approaches is used. DSC is used to measure the heat flow of the drug substance-excipient combinations to look for any changes in thermal behaviour that can indicate compatibility or incompatibility TGA.^13,14

The relationship between host and visitor was studied using FTIR spectroscopy. Powder XRD might be used to identify pure-phase crystalline or multiphase MOFs materials. TGA to provide drug loading and stability information in the MOF matrix, using DSC to investigate the shape of the cargo in MOFs and assess their interaction. FTIR, DSC investigates probable chemical interactions between VIN and the excipients and thermal investigation. A Rigaku Ultima IV X-ray Diffractometer was used to perform XRD studies on VIN and VIN nanoparticles. DSC was used to assess the physical state of the candidate drug within the optimised LPH. The free candidate drug, drug-loaded LPH nanoparticles, and blank LPH nanoparticles were precisely weighed and encapsulated in aluminium pans showing that the drug had been transformed into an amorphous state because of its encapsulation in LPH nanoparticles.^15,16,17

The FT-IR Spectrophotometer is used to identify Fluoxetine HCl. This finding is significant since it clearly shows that the formulation has no obvious drug-polymer interactions at the molecular level. The examination and determination of the potential interactions between sildenafil and various excipients included FTIR and X-ray powder diffraction methods. The development of efficient and reliable pharmaceutical goods is aided by the combination of TGA, DSC, XRD, and FTIR, which enables a thorough evaluation of their compatibility^18,19. XRD and DSC assessed crystallinity and phase transition; FTIR revealed PC-RN interaction with weak bonding. DSC, FTIR, and XRD analyses showed RN's higher crystallinity, RN-PC compatibility with weak bonding, and PC-RN interaction lowering phase transition temps. FTIR spectroscopy was employed to investigate potential drug-polymer interactions, and DSC analysis identified the presence of an amorphous state within the SDs. FTIR analysis found no evidence of drug-polymer interactions in the SDs, while DSC revealed that the SDs were in an amorphous state, enhancing drug solubility^{20, 21}

The study explores the use of biodegradable materials in nanoparticle-based drug delivery systems, specifically hydroxyapatite (HA). HA's strong affinity for bone tissue makes it an effective substitute for oral vitamin D administration. The HA-VD composite, a codelivery system, provides both VD and Ca3(PO4)2, and is biocompatible. The enteric polymer HP-55 is electrosprayed over HA to create resistant particles. Infrared spectra were obtained in the wave number range of 4,000–400 cm⁻¹ using an FTIR spectrophotometer. The crystalline behavior of HA is shown by the XRD pattern, which has significant extraneous peaks at 31–32, 49–50, and 25–27 (2θ angle). The main peaks in HP-55 coated HA are at 950, 1072, 1286, 1720, 2895, and 3475 cm-1, whereas in pure HP-55 they are at 950, 1052, 1263, 1715, 2933, and 3448 cm-1. The materials performed a potassium bromide pellet procedure to prepare them for FTIR analysis. FTIR spectra were recorded between 4000 and 400 cm⁻¹ at a resolution of 4 cm⁻¹. The glass transition temperature of the AQ was further confirmed with the use of DSC-60 for differential scanning calorimetry (DSC) investigation. TGA, DSC, and CD studies provided crucial proof that BSA kept its original structure even after adsorption on AQ. Aquasome is a dual medication carrier that can be used for various illnesses. It was created and characterized using Raman spectroscopy, and BSA maintained its original structure even after adsorption.^22,23,24

Using a diffractometer, X-ray powder diffraction (XRD) was applied to Duloxetine HCl to examine its polymorphic state. Operating at 40 kV and 35mA, the Si (Li) PSD detector recorded data from 3 to 1500 over a 30-second scanning period. The incorporation of ssDNA was confirmed by an FTIR peak at 1050 cm−1, and the loading of 28 was measured using dynamic light scattering and zeta potential. CpGs were immobilized on isMOF, and TGA was used to validate drug loading and evaluate drug resistance to deterioration. The niosomal suspension sample of pure Buspirone hydrochloride (BH) was weighed and placed in conventional aluminium pans for packaging. The temperature range of 30°C to 350°C was scanned at a rate of 10°C/min to get sample thermograms. Two endothermic peaks were displayed by buspirone hydrochloride (190.49°C and 204.72°C). The crystalline substance known as pure buspiron hydrochloride has many distinct peaks with diffraction angles of 30°, 198°, 1220°, and 580°.^25,26,27The dried LRD material (about 1 mg) was loaded and sealed into the DSC pan using a DSC loading puncher. The sample was heated at a rate of 5 degrees Celsius per minute in an inert nitrogen atmosphere while being scanned between 40 and 400 degrees Celsius using a differential scanning calorimeter, Perkin Elmer Pyris 6 DSC (Perkin Elmer, Waltham, MA).Samples were heated in a nitrogen atmosphere to validate the physical state melting and recrystallizing behaviour of matrix lipids, which are crucial for producing SLNs. DSC thermograms of bulk lipids and SLNs often differ in position and shape. The DSC curve of Naratriptan, a pure medicine, shows it as crystalline anhydrous with a significant endothermic peak at 2430 C, corresponding to its melting point of 239 0 C.The study concluded that using a combination of egg lecithin and Poloxamer 188 concentrations in an ideal formulation achieves a narrower size and sustained drug release, potentially reducing the need for frequent drug administration. FTIR analysis demonstrated the incorporation of the drug into NLCs by showing relevant spectral changes. XRD analysis indicated changes in the crystalline properties of the system, suggesting drug incorporation into NLCs. DSC analysis revealed alterations in the thermal properties, supporting the incorporation of the drug into NLCs.^28,29,30

Applications in Pharmaceutical Compatibility Studies:

The combination of these methods offers a thorough evaluation of medication compatibility. While DSC, XRD, and TGA provide information about the physical and thermal properties of the formulation, FTIR can be used by researchers to spot probable chemical interactions between therapeutic components.

1. Detection of Incompatibilities:

Chemical reactions, phase separation, or crystalline changes can all lead to incompatibilities. Chemical incompatibilities can be found using FTIR, while phase shifts and polymorphism can be found using DSC and XRD. Thermal instability can be localized via TGA.

2. Formulation Development:

Understanding medication compatibility is essential when developing a formulation. These methods help in the proper excipient selection and the optimization of drug delivery systems for improved stability and bioavailability.

3. Stability Testing:

Pharmaceutical stability studies benefit from these techniques, as they help identify potential issues related to long-term storage and shelf-life of drug products.

The Table 1 shows the comparison of the given four methods which are FTIR, DSC, XRD and TGA with the algorithm used in all the four methods and comparing them by their advantages and disadvantages.

Table.1 Comparison of FTIR, DSC, XRD and TGA.

Sr No.	Method	Algorithm used	Advantages	Disadvantages
1	FTIR	This study employs FTIR spectroscopy to assess drug compatibility, utilizing spectral analysis to identify potential interactions and chemical changes, facilitating a comprehensive characterization of drug interactions and their implications.	Non-destructive, rapid, and offers qualitative and quantitative analysis of drug interactions. Provides information about chemical bonds and functional groups.	Limited to surface analysis, may not detect subtle interactions, and cannot determine the degree of compatibility.
2	DSC	In this study, Drug Compatibility is characterized through DSC, which measures thermal transitions to assess potential interactions, providing valuable insights into the stability and compatibility of drugs in various formulations.	Detects phase transitions, melting points, and heat capacity changes, aiding in compatibility assessment. Offers valuable information about energy changes in drug interactions.	Does not provide structural information, may not detect subtle interactions, and requires careful sample preparation.
3	XRD	This research utilizes XRD analysis to investigate drug compatibility, employing XRD patterns to identify and characterize crystalline structures and potential changes in drug formulations for comprehensive compatibility assessment.	Accurately identifies crystalline structures, polymorphs, and changes in drug formulations. Suitable for detecting solid-state interactions.	Requires extensive sample preparation, may not identify amorphous structures, and is not as informative about molecular-level interactions.
4	TGA	This study employs TGA to assess drug compatibility, analysing the weight loss and thermal behavior of drug formulations to determine potential interactions and stability, offering a comprehensive characterization of drug compatibility.	Determines thermal stability and decomposition temperature, offers insights into mass changes. Valuable for identifying degradation and compatibility issues.	Provides limited chemical information, not effective for amorphous materials, and cannot distinguish between multiple components.

CONCLUSION:

The characterization of drug compatibility through analytical techniques such as FTIR, DSC, XRD, and TGA plays a pivotal role in pharmaceutical development. These methods provide valuable insights into potential chemical and physical interactions between active pharmaceutical ingredients (APIs) and excipients, enabling the creation of safe and effective drug formulations. By detecting incompatibilities, elucidating phase transitions, and assessing thermal stability, these techniques contribute to improved product quality, stability, and bioavailability. The presented review study extensively covers the applications and advantages of each method, highlighting their relevance in pharmaceutical compatibility assessment, formulation development, and stability testing. Furthermore, the integration of FTIR, DSC, XRD, and TGA offers a holistic approach to understanding drug compatibility, allowing researchers to identify both chemical and physical changes in drug formulations. This comprehensive perspective is crucial for ensuring the effectiveness and safety of pharmaceutical products, emphasizing the critical role of compatibility studies in the pharmaceutical industry. The references cited in this review paper reflect the diverse applications and advancements in the field of drug compatibility studies. These methodologies not only enhance our understanding of API-excipient interactions but also contribute to the development of innovative drug delivery systems and the optimization of pharmaceutical formulations. Overall, this comprehensive review provides a valuable resource for researchers and pharmaceutical scientists, guiding them in creating secure and efficient drug combinations and ensuring the effectiveness and safety of pharmaceutical products.

FUTURE SCOPE:

The review focuses on an important and ever-changing part of pharmaceutical research. Understanding the compatibility of medications with excipients is critical as the pharmaceutical industry seeks to design safe and effective therapeutic formulations. This review article not only provides a comprehensive overview of current methodologies and techniques used in drug-excipient compatibility studies, but it also highlights their structural and functional aspects using various analytical tools such as FTIR, DSC, XRD, and TGA. Furthermore, the study serves as a basis for future research in the topic. As new medications and excipients are created, their compatibility must be evaluated on an ongoing basis. Emerging analytical techniques and technologies may improve the precision and efficiency of these research, and the review article can serve as a resource for incorporating these advancements.

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Received on 22.03.2024 Revised on 17.07.2024

Accepted on 05.09.2024 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1434-1438.

DOI: 10.52711/0974-360X.2025.00206

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.