Characterization and Reverse Engineering of Pharmaceuticals:

Role of Thermoanalytical Techniques


Gobardhan Bal1, Lakshmi K1, Rajkumar M2, Bibhash C. Mohanta3*

1Chettinad School of Pharmaceutical Sciences, Chettinad Hospital and Research Institute,

Chettinad Academy of Research and Education, Kelambakkam - 603103, Tamil Nadu, India.

2Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER),

Hajipur - 844102, Bihar, India.

3Department of Pharmacy, Central University of South Bihar, Gaya - 824236, Bihar, India.

*Corresponding Author E-mail:



During pharmaceutical or biopharmaceutical drug product development, one of the most important steps to be followed is characterization and reverse engineering of the drug product. Out of so many characterization tools and orthogonal reverse engineering techniques, thermoanalytical methods are the most useful techniques. Different thermoanalytical techniques are used to identify, quantify and understand the interaction between different polymorphic forms of drug substances and excipients. These techniques are also used to monitor the physical form (amorphous or crystalline) of the drug substance in drug product throughout its manufacturing processes and helps in identifying, omitting or modifying the steps or processes responsible for change in physical or polymorphic form of the drug substance in the finished drug product. Thermoanalytical techniques are not only useful for characterization of small molecules but also extensively applied in analysis of biological samples and nano-formulations. In current scenario, pharmaceutical development specifically during generic drug development the most useful step is the reverse engineering. When reverse engineering of drug product is concerned, thermoanalytical techniques are the best tools to be used to prove the similarity of physico-chemical properties or same state of matter or arrangement of matter between test and reference products. However, in earlier days these techniques were not used as frequently as the other techniques like spectroscopy and chromatography. Various reasons for limited use of thermoanalytical techniques were unavailability of software or compatible hardware, manual sampling process and a tedious process of manual calculation which consumes lots of time. Now a day, due to advancement of technology, automation, use of robotics, and better understanding, and the thermal analysis not only become a powerful tool but also increase the throughput. The present review focuses on some of the most commonly used Thermoanalytical techniques e.g. Differential Scanning Calorimeter (DSC), Thermogravimetric Analysis (TGA), Solution Calorimeter (SC), Thermo Mechanical Analysis (TMA) and Isothermal Titration Calorimeter (ITC) for characterization and reverse engineering of different dosage forms like solid oral dosage forms, injectable formulation, inhalation formulation, ophthalmic formulation, and biosimilar formulation products such as peptides and proteins using specific case studies.


KEYWORDS: Reverse-engineering, Characterization, Differential Scanning Calorimeter (DSC), Thermogravimetric Analysis (TGA), Thermoanalytical Techniques, Thermo Mechanical Analysis (TMA), Isothermal Titration Calorimeter (ITC), Solution Calorimeter (SC).




The most important step of drug product development is to check the quality and to establish the safety and efficacy of the developed product. For submitting a new drug applications (NDA) the applicant must have to prove the safety and efficacy of the product. However, while submitting an abbreviated new drug application (ANDA), the applicant need not have to prove the safety and efficacy of the product, as ANDA relies on the safety and efficacy data of the reference listed drug product approved by the FDA. The ANDA applicant must demonstrate that its drug product is bioequivalent to the reference listed drug.1 For an ANDA, bioequivalence testing of drug product is the highest cost involved affairs and also sometimes it is not feasible to perform the bioequivalence study for certain drug products. To encourage the development of generic drug product, USFDA has initiated several policies to streamline the bioequivalence study.


The main challenges for ANDA applicants are similarity assessment of both the test and the reference products which are required during submission of application to regulatory authority for product approval or to understand the product during development stage. Several conventional, non-conventional, and orthogonal techniques are used to find, and evaluate the similarity between the test and the reference products.2 When thermoanalytical techniques are concerned they are less focused in comparison to other techniques like microscopy, spectroscopy, chromatography and others. As per the USFDA, the similarity of drug products is categorized into Q1(qualitatively same), Q2(quantitatively same) and Q3(same physico-chemical properties or same state of matter or arrangement of matter)3. Among several techniques, the thermoanalytical techniques are most preferable techniques to map the Q3 similarity. During pharmaceutical product development, thermoanalytical techniques are also conventionally used for development and routine analysis of drug substance as well as drug products. The advantages of thermoanalytical method in comparison to other methods are (i) helps to understand the change in physico-chemical properties of the drug substance and drug product in a real time manner with respect to time and temperature (ii) need very less sample quality for analysis (iii) shorter analysis time (iv) lesser sample preparation and processing error (v) useful in both qualitative and quantitative analysis. In research and development, we cannot disagree with the notation “Thermal method is the late fruit of the love of researcher to analyse matter”.4


In current scenario of pharmaceutical development specifically for generic drug development the most useful step is reverse engineering. When reverse engineering of drug product is concerned, thermoanalytical techniques are the best tools to be used.5 However, in earlier days these techniques were not used as frequently as the other techniques like spectroscopy and chromatography are used. Various reasons for less use of thermoanalytical techniques were unavailability of software or compatible hardware and sample analysis as well as calculation was complete manual tedious process which consumes lots of time. Now a day, due to advancement of technology, automation, use of robotics, and better understanding, the thermal analysis not only become a powerful tool but also increase the throughput.6


To develop a stable medicinal product, it is necessary to understand the response of drug and its formulation to thermal stress. Thermoanalytical methods are precise and accurate techniques which use very low quantity of sample and provide details information about the new drug substances as well as drug products at early stage of drug discovery and development.7 Thermoanalytical techniques are also extensively used in analysis of biological samples (proteins, nucleic acid, lipid, carbohydrates, and monoclonal antibodies) and nanoparticles (lipid based nano carriers, polymeric nanoparticle, ion chelated nano carriers). 8


The present review focuses on some of the mostly used thermoanalytical techniques like Differential Scanning Calorimeter (DSC), Thermogravimetric Analysis (TGA), Solution Calorimeter (SC), Thermo Mechanical Analysis (TMA), and Isothermal Titration Calorimeter (ITC) for characterization and reverse engineering of different dosage forms like solid oral dosage forms, injectable formulation, inhalation formulation, ophthalmic formulation and biosimilar formulation products like peptides and proteins using specific case studies.


Thermo Analytical Techniques:

Thermo-analytical techniques are most commonly used techniques in pharmaceutical product development where the changes in physico-chemical properties of active pharmaceutical ingredients or drug products are studied with respect to temperature or time. One of the major advantages of thermo analytical techniques is that they can be coupled with one another to give more understanding about the product characteristic. Some of the commonly used thermo analytical instruments in pharmaceutical development are Differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA), Solution calorimeter, Thermo mechanical analysis (TMA), and Isothermal titration calorimeter (ITC).9 Some commonly used thermoanalytical techniques with their application are depicted in Table-1.


Differential Scanning Calorimetry (DSC):

Differential scanning calorimetry (DSC) is the most widely used thermoanalytical technique in pharmaceutical industries. It can be used for both qualitative and quantitative analysis of drug substances and the finished drug product. DSC works on the principle of change in heat flow with respect to temperature and time. 10 Basically in terms of instrumentation principle there are two types of DSC instruments (a) Heat flux DSC and (b) Power compensation DSC. In case of heat flux DSC, a single furnace is used to heat both the sample and reference and the temperature difference obtained between the sample and reference is measured. In case of power compensated DSC two different furnaces are used to heat both sample and reference separately in such a way that the temperature of the sample and reference are maintained identical. The difference in power which is necessary to maintain the temperature is measured.11


Differential scanning calorimetry provides a rapid and accurate method for physico-chemical characterization of both drug substances and drug product. The quantity of sample required for analysis is very less in comparison to other techniques.12 However, the limitation of the method is that the compounds which decompose on melting cannot be used for analysis. DSC can provide support in understanding the product in many areas which is not possible by other methods and also provide additional evidence to interpret and conclude the data that obtained by other orthogonal techniques.13,14 From DSC thermogram, different thermal events are interpreted like glass transition, crystallization, melting and degradation depending on the nature of the material.15,16


Table No: 1 Commonly Used Thermoanalytical Techniques

Name of the Instrument

Properties Measured


Differential Scanning Calorimetry


Change in heat flow

Glass Transition, Melting, Polymorphism phase diagram, Heat capacity, Enthalpy, Purity, Decomposition

Thermogravimetric Analysis


Change in mass/weight

Thermal and oxidative stability, Decomposition kinetics, Moisture and volatile content, Loss on drying

Solution Calorimeter (SC)

Heat of dissolution

% Crystallinity

Thermomechanical Analysis (TMA)

Change in dimension or deformation

Deformation and change in dimension

Isothermal Titration Calorimeter (ITC)

Change in heat flow

Binding affinity and bimolecular interaction


Thermogravimetric Analysis (TGA):

TGA is one of the oldest thermoanalytical technique used extensively in the study of material sciences. Principle of TGA involves measuring the change in mass or weight of sample in a chosen controlled atmosphere (nitrogen or air) as function of temperature or time.11 TGA instrument contains various components like heating furnace, temperature programmer, electronic microbalance and sample holder.17 When a temperature program is applied to the furnace containing the electronic microbalance with sample holder, it allows the sample to be simultaneously weighed and heated in a control manner. The changes in weight or mass are recorded against temperature and time. In pharmaceutical research and development TGA is used to understand many thermal event of drug substances and drug products like absorption, adsorption, desorption, vaporization, sublimation, decomposition, oxidation and reduction.18 Limitation of TGA is that it cannot identify the chemical composition of lost mass or solvent. However, to understand more about the chemical nature of lost mass of volatile solvent TGA can be coupled with other techniques like DSC, IR, GC or GCMS.


Solution Calorimeter(SC):

Solution calorimeter is the most useful instrument to identify and quantify the amorphous and crystalline nature of material with high accuracy and precision. It can be used to detect very less amount of amorphous content up to trace level. Solution calorimeter work on the principle of measuring the heat of dissolution when a solid is dissolved in a liquid, or two liquids are mixed. It measures the amount of change in heat during the process of dissolution. It comprises of a thermostatic bath which maintain the programmed temperature throughout the experiment, a vessel to hold the solvent, an ampoule for sample loading and a stirring system to ensure proper mixing during the dissolution process. The sample inside the ampoule is properly separated from the solvent; at a particular time (as per the program after equilibrium and calibration) it will be allowed to dissolve by rupturing the glass ampoule and the heat evolved or consumed are measured during the dissolution process.


The advantage of solution calorimetry analysis is that the system gets calibrated two times in a single experiment i.e. before breaking and after breaking. Before breaking the ampoule, the calorimeter was calibrated by using a known amount of heat supplied by the system and once again by the same process after breaking the ampoule19. The enthalpy of the solution of the solute was determined by measuring the change in temperature during the dissolution process after breaking the ampoule. 


Thermomechanical Analysis (TMA):

TMA is one of the commonly used thermoanalytical techniques in the field of pharmaceutical research especially when the change in dimension or deformation of material is considered. The working principle of TMA is the measurement of the change in dimension or deformation of sample material under a non-oscillating stress with respect to temperature and time20. TMA instrument comprises of a sample holder, a thermocouple, a furnace and a sensor. When a temperature program is applied to the sample through the furnace the change in dimension or deformation will be measured by the sensor. A typical TMA thermogram gives the complete degradation profile (start time, rate and duration of different processes like swelling and disintegration) with respect to time or temperature. The construction and arrangement of sample holder can be fabricated as per the experimental purpose considering the sample to be tested.


Isothermal Titration Calorimeter (ITC):

ITC is used for quantitative studies of bio-molecular interaction. This method helps to understand complete thermodynamic profile and all binding parameters of molecular Interaction. It is generally used for characterization of biomolecules. Basic principle of ITC is same as a heat flux calorimeter. It measures the amount of power required to maintain a constant temperature difference between sample and reference cell21. The components of ITC instruments are two coil shaped cells (Sample and Reference), a thermostat jacket, a feedback control system to monitor the temperature difference between sample and reference cells, and an injection syringe system to add the reactants to sample cell.



Most of the time it was considered that the thermal methods are useful for compatibility study of drug substance and excipients, but in real case thermal methods are extensively used for several other purposes like qualitative and quantitative analysis, understanding impact of manufacturing process and stability analysis. Advancement in both hardware and software of instrument make easy aces for different types of drug product formulation like solid dosage form, injectable products, inhalation products, ophthalmic product, biologics, and biosimilar. In generic drug product development these techniques help to determine the physico-chemical similarity between test and reference product. The most critical and challenging part in analysis of different dosage form is sample preparation, because there are a lot of chances that the polymorphic or physical form of drug substance or excipient may change during sample preparation which may mislead the interpretation of results.


Solid Oral Formulations:

For characterization and reverse engineering of solid dosage forms like tablets and capsules, thermoanalytical techniques are extensively used22-31. Presence of crystalline or amorphous content of drug substance plays an important role in drug dissolution, absorption and bioavailability. Prior to drug development it is highly recommended to determine the amorphous or crystalline content of drug substances.


High speed DSC (Hyper-DSC) can be used to detect and quantify amorphous content present in mostly crystalline sample where the amorphous content present in negligible amount.32 DSC and TGA can also be used to find out the critical quality attribute for thermal instability of tablets. In a case study,33 after investigating the thermal behaviour of Chloramphenicol and its various mixtures with different excipients by TGA and DSC it was observed that the Chloramphenicol base was thermally more stable than the tablet formulation. The reason for decrease in thermal stability of Chloramphenicol tablet in comparison to Chloramphenicol base (drug substance) was due to presence of water content in starch. The other excipients used in the tablet were not significantly influencing the temperature of degradation of Chloramphenicol in Chloramphenicol tablets.


TGA can be used to establish pharmaceutical equivalence between reference and test product using thermal decomposition reaction rate constant and dissolution kinetic rate constants.34 Thermal techniques can also be used for quantitative analysis.35 In another case study, DSC was used to quantity different active ingredients dispersed in polymers. Different active ingredients were used with a polymer to cast a 1mm thickness of film. Different amount of film above the detection limit and pure drug substances were analysed. The DSC data were interpreted and the concentration of drug present in the polymer was calculated. It was also observed from the DSC study that one of the drugs lost its original polymorphic form and converted to other polymorphic forms.


Solution calorimetry is generally used to estimate the amorphous content of a compound using a solvent in which the compound is highly soluble.36 Solution calorimetry can also be used to investigate the interaction of drug with the simulated intestinal fluid (SIF). A study was conducted by taking two model drugs mannitol (hydrophilic) and propranolol (hydrophobic) as solute. Simulated intestinal fluid was used to mimic both the fed and fasted states. Hanks’ balanced salt solutions of different pH are used as solvent. During the experiment both the solutes exhibited endothermic reaction in all the solvent. After the experimentation and data interpretation, it was noticed that there was an interaction between propranolol and the micellar phase of both fasting and fed states of SIF whereas mannitol showed a minimal interaction with micellar phases of SIF.37


TMA is used for measuring the change in dimension and deformation. Isothermal TMA equipment was used to characterize tablet (solid dosage forms) for understanding the disintegration process. Tablets were analysed by measuring the swelling, shrinkage and disintegration process in a specified liquid medium with respect to time, temperature, applied stress and pH of the liquid medium. The isothermal TMA was a better option to study the disintegration process as compared to USP disintegration test apparatus. The USP disintegration test apparatus provides only the time of disintegration whereas TMA provides the start time of disintegration as well as the rate of disintegration. Moreover, the full pattern of disintegration process could also be understood from TMA result. The time when swelling and disintegration start and duration of that process can also be captured. Most importantly the quantitative results can be obtained after the experiment.38


Injectable formulations:

The thermoanalytical methods are also frequently used for characterization of complex injectable formulations such as long acting injectable, suspensions, microspheres, nanoparticles and depot formulations. One of the important applications is evaluation of crystal forms of the drug in each step of the manufacturing process of suspension dosage form administered as a long acting injection. It was reported that different crystal forms give different dissolution results. Thus it is highly essential to control the crystal form of the drug as dissolution process has great impact on the product quality. In this case study, during the wet grinding process of a suspension injection, different grinding times were used in an increasing order to achieve particle of different size ranges that were analysed by DSC and TGA to ensure the crystal forms. As the grinding time increases the particle size of the drug decreases which was confirmed by particle size distribution data. From the combined data analysis, interpretation and correlation of DSC thermogram, TGA thermogram and Particle size histogram it was concluded that the crystal form does not change during the grinding process.39


DSC can be used for characterization of gelatin microspheres.40 Liposomes are generally used for delivering the drug to a specific targeted site. DSC is a functional tool for designing lipidic drug delivery systems like liposomes. The substances that are mixed to prepare liposome can be estimated and there by divulge justification of liposomal composition. Through DSC, investigation of any alternation in thermodynamic behaviour of lipid bilayer after drug encapsulation in liposome can be done. Alternation in the thermodynamic behaviour could be related to the interactions of the drug with the lipid carrier that adversely affect the drug bioavailability as well as stability of the liposomal preparation.


Thus, DSC technique could be used to investigate unilamellar vesicles (small unilamellar, large unilamellar vesicles), multilamellar vesicles where lipids are present in supported bilayer.41


Aerosol formulations (DPI/MDI):

Efficacy of Aerosol product (MDI/DPI) depends on the physico-chemical characteristics of drug particles or droplets emitted after actuation from the device. It may be possible that different formulations are quantitatively and qualitatively same but it is also highly essential to ensure that the polymorphic forms, solvent content of emitted particle are same for different formulation. Thermoanalytical methods play a crucial role to characterize those properties of actuated drug products. The sample preparations for thermoanalytical method to be used for aerosol products are somewhat lengthy and complex. The samples need to be actuated through the Cascade impactor or next generation pharmaceutical impactor (NGI) and after that the sample from different compartments will be collected and analysed.


Solution composition of pressurized metered-dose inhaler (pMDI) plays an important role during particle formation from the droplet emitted after actuation. Different composition of solutions forms particle of different physico-chemical characteristics even though they have same aerodynamic performance. So during the development of pMDI products the focus should be given to not only the particle size of the product but also to the particle characteristic to assure bioequivalence.42


The most important analysis of solution inhalation formulation is characterization of droplets/particles emitted after actuation because these droplets only plays important role in absorption and bioavailability. In this case the thermoanalytical techniques reveal the actual crystalline or amorphous nature of the collected particles/droplet.43


Ophthalmic Formulations:

In case of ophthalmic suspension products, physicochemical properties of drug substances suspended in the formulation play an important role for its in vivo performance. During the manufacturing process of ophthalmic suspension product, high energy inputs are given to the suspension (e.g. autoclaving and Milling) which could change the polymorphic form of the input drug substances. So it is essential to find out the polymorphic form of drug substance in the finished product. DSC can be used to find out the polymorphic form of the drug substances in the ophthalmic suspension formulation. Different formulation with different input energy can be analysed to compare the thermal behaviour with that of pure drug substance, placebo, physical mixture and commercial drug product. In a case study the relationship between the melting temperature and particle size of the formulation was observed.44 Decrease in particle size (increase in surface area) causes the shifting of melting temperature towards lower side. Lower the particle size lower the melting temperature. The shifting of melting temperature was also observed in the physical mixture. So it was concluded that the shift in melting point may be due to the molecular interaction of drug with excipient and also supported by decreasing particle size. In another example drug and excipient complexation was formulated to enhance the trans-corneal permeation of the drug.45 The formation of the complexation was confirmed by analysis using DSC. Different samples of drug substance, excipient and various mixtures (Dry mixer, Kneaded mixture, Freeze dried and Rotavap mixture) were analysed using DSC to prove the hypothesis.


Biosimilar formulations:

For biosimilar product (includes proteins46-47, peptides, and monoclonal antibodies48), the stability of the drug product is important in both drug delivery system and physiological condition. Thermal methods are very important to ensure the stability, denaturation, and folding unfolding states of biosimilar products49. DSC is one of the most useful instrumental tools to predict the long term aggregation stability of proteins.50-53 For proteins and peptide two important parameters interpreted in DSC are phase transition temperature (Tm) and enthalpy. Tm is defined as the mid phase transition temperature at which 50% of the drug is in folded states and 50% at unfolded or denaturated state. Higher the Tm higher the stability of the sample it means if the drug starts unfolding at high temperature there is less chance of non-native aggregation over time. DSC is used routinely to monitor Tm and enthalpy of proteins and peptides which is a critical parameter to decide stability of the formulation.



Thermoanalytical techniques have a wide range of application with respect to characterization and reverse engineering of drug products. The purpose of this article is to explore the thermoanalytical techniques which are very much useful but not emphasised in drug development. These techniques are used to better understand the physical and polymorphic state of drug substances which are embedded in drug product. Physical state of the drug substances has high impact on the bioavailability of the product which decides the safety and efficacy of the product. These techniques are used in both new drug development and generic drug development. In new drug development stage it helps to optimize the best suitable form of the new drug substance having good stability, solubility and compatibility with different excipients for new formulation development. In generic drug development it is useful to understand the physico-chemical characteristic of the reference product which helps to develop the test product similar to the reference product. Most importantly thermoanalytical techniques are not only useful for analysis of drug substance but also can be used extensively for characterization various dosage form. The product information and understanding obtained from the results of thermal analysis cannot be provided by any other techniques so these are the best orthogonal techniques for pharmaceutical product development.


List of Abbreviation:

ANDA: Abbreviated New Drug Application; DSC: Differential Scanning Calorimeter; GC: Gas chromatography; GCMS: Gas Chromatography Mass Spectroscopy; IR: Infrared; IsoTMA: Isothermo Mechanical Analysis; ITC: Isothermal Titration Calorimeter; NDA: New drug applications; SC: Solution Calorimeter; SIF: Simulated Intestinal Fluid; TGA: Thermogravimatric Analysis; TMA: Thermo Mechanical Analysis; USFDA: United State Food & Drug Administration;



There is no conflict of interest.



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Received on 12.10.2022            Modified on 28.03.2023

Accepted on 16.08.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(10):4973-4980.

DOI: 10.52711/0974-360X.2023.00805