The coupling of TG devices with non-thermal techniques has proven remarkably useful. Data obtained using coupled TG systems with FTIR, MS or GC/MS are crucial from the viewpoint of drug formulation technology. They make it possible to know exactly how APIs behave during heating, identify volatile degradation products and determine the mechanism of thermal degradation. These data make it possible to predict the behavior of APIs during the manufacture of pharmaceutical formulations and enable the determination of their shelf life and storage conditions.
3.1. TG Coupled to FTIR Spectrometer
Of all the techniques coupled to the TG device, TG–FTIR is the simplest and, at the same time, the most widely used coupled system in pharmaceutical studies. A block diagram of the TG–FTIR equipment is shown in
Figure 3. In addition to the TG and FTIR devices, the most important element of this system is the interface, which connects the TG device to the FTIR spectrometer [
14,
15,
16]. The interface includes the measurement chamber (gas cell) of the FTIR spectrometer and a connector (transfer line) that connects the outlet of the TG oven to the inlet of the measurement chamber of the FTIR spectrometer.
The measurement cell is installed in the light line between the interferometer and the detector. The measurement chamber and the connector are maintained at a certain temperature, which prevents condensation of volatile degradation products on the inner walls of these components. The most suitable temperature at which the measuring chamber and connector should be maintained is that at which no thermal degradation of the sample under study occurs. In turn, the carrier gas carrying the volatile degradation products from the TG oven to the measuring chamber of the FTIR spectrometer is the same gas in which the sample was explored in the TG furnace. It should be mentioned that both inert and oxidizing gas atmospheres can be used for TG–FTIR.
Literature data showed that coupled TG–FTIR systems have been widely used for studying APIs, while no example was found of the use of TG–FTIR for studying pharmaceutical preparations (tablets, capsules, irritants). It should also be mentioned that the equipment and measurement conditions used for the study varied widely, as shown in
Table 1. Analysis of these data indicates that a device from TA Instruments, model SDT-Q600 TG/DTG/DTA, and an FTIR spectrometer from Thermo Scientific, model Nicolet iS10, were most often used to study APIs.
Volatile degradation products were obtained by decomposing the samples in a TG device. Various mass samples were used, usually 10 mg [
22,
23,
24,
25,
26,
27], 12–15 mg [
28,
29,
30,
31,
32] or 15–20 mg [
24,
33]. Samples in open α-alumina sample holders [
24,
25,
26,
27,
28,
29,
30,
31,
32] or ceramic crucibles [
34] were heated from ambient temperature to 400 °C [
26,
27], 500 °C [
34], 700 °C [
35] or 800 °C [
22,
23]; at heating rates of 5 °C/min [
34], 10 °C/min [
28,
29,
30,
31,
32] or 20 °C/min [
22,
23,
24,
25,
26,
27,
35]; in dry nitrogen [
22,
23,
26,
27,
28,
29,
30,
31,
32,
34,
35] or dry air [
22,
23,
24,
25,
35]; and at flow rates of 20 mL/min [
34], 50 mL/min [
24,
25,
28,
29,
30], 60 mL/min [
31,
32], 80 mL/min [
35] or 100 mL/min [
22,
23,
26,
27].
The data summarized in
Table 1 also indicate that the connector between both instruments, i.e., the TG device and the FTIR spectrometer, with a length of 120 cm and an inner diameter of 2–3 mm, was made of stainless steel. In only one case, the connector was made of Teflon. The connector and the measuring chamber of the FTIR spectrometer were mostly maintained in the temperature range of 200–270 °C. In only one case, both elements were not heated and were kept at 25 °C. On the other hand, FTIR spectra were recorded in the spectral range from 4000 cm
–1 to 675–400 cm
–1, most often with a resolution of 4 cm
–1, using a Deuterated TriGlycine Sulfate (DTGS) detector. The interferometer and the gas cell compartment were purged with nitrogen [
28,
29].
Table 1.
TG–FTIR coupled systems used in the study of active pharmaceutical ingredients.
Table 1.
TG–FTIR coupled systems used in the study of active pharmaceutical ingredients.
TG Instruments | FTIR Spectrometers | Transfer Line | FTIR Spectra Measurements | References |
---|
SDT-Q600 TG/DTG/DTA (TA Instruments) | Nicolet iS10 FTIR (Thermo Scientific) | stainless steel tube, l = 120 cm, ø = 2 mm; 200 °C, 220 °C, 225 °C, 230 °C | 200 °C, 220 °C, 250 °C; nitrogen, flow rate 50 mL/min; 4000–500 cm–1, 32 scans, 4 cm–1, 6 cm–1; DTGS (KBr) | [22,23,28,29,30,31,32,35,36] |
TGA/DSC Stare (Mettler-Toledo) | Nicolet iS10 FTIR (Thermo Scientific) | stainless steel tube, l = 120 cm, ø = 3 mm; 25 °C, 200 °C | 25 °C, 250 °C; air, flow rate 50 mL/min; 4000–600 cm–1, 32 scans, 4 cm–1; DTGS (KBr) | [24,25,37] |
TGA/SDTA 851 (Mettler-Toledo) | Nicolet iS10 FTIR (Thermo Scientific) | | | [38] |
TG-DSC 1 (Mettler-Toledo) | FTIR Nicolet (Thermo Scientific) | stainless steel tube, l = 120 cm, ø = 3 mm; 225 °C | 250 °C; air, nitrogen, flow rate 50 mL/min; 4000–675 cm–1, 16 scans, 4 cm–1; DTGS (ZnSe, KBr) | [39,40,41,42] |
SDT-Q600 TG/DTG/DTA (TA Instruments) | Nicolet 6700 FTIR (Thermo Fisher Scientific) | | 8 scans, 4 cm–1; MCT-A | [33] |
TGA 2950 (TA Instruments) | Nexus 470 FTIR (Thermo/Nicolet) | 250 °C | 250 °C; air; 4000–450 cm–1, 32 scans, 4 cm–1 | [43] |
TG 2050 (TA Instruments) | FTS 3000 IR (BioRad Excalibur) | stainless steel tube | 4 cm–1 | [44] |
STA 6000 TG (Perkin Elmer) | Frontier FTIR (Perkin Elmer) | 270 °C | 4000–450 cm–1 | [34] |
Diamond TG/DTG/DTA (Perkin Elmer) | Spectrum 100 (Perkin Elmer) | | | [45] |
STA 449 Jupiter F1 TG/DTG/DSC (Netzsch) | FTIR TGA 585 (Bruker) | Teflon transfer line, ø = 2 mm; 200 °C | 200 °C; 4000–600 cm–1, 16 scans, 4 cm–1 | [46] |
TG 209 (Netzsch) | IFS 66 (Bruker) | | | [47] |
Setsys 16 TG-DTA/DSC (Setaram) | Thermo Nicolet Nexus 670 FTIR (Thermo Scientific) | stainless steel tube, l = 100 cm, ø = 3 mm, 200 °C | 200 °C; 8 scans, 8 cm–1 | [26,27] |
Recently, a new instrument for TG–FTIR was introduced to the market, in which an apparatus for simultaneous TG–DSC measurements (STA 449 Jupiter, Netzsch) was directly coupled to an FTIR spectrometer (Bruker) without the use of a transfer line [
48]. Mounting the FTIR spectrometer with very small dimensions directly on the top cover of the TG furnace eliminates the time delay in recording FTIR spectra due to the volume of volatile degradation products in the transfer line. The utility of this apparatus for evolved gas analysis was confirmed by studying the degradation of naphthalene, straw and topaz (a mineral).
Table 2 shows the general characteristics of APIs studying with coupled TG–FTIR systems. These data indicate that identifying volatile degradation products is one of the basic conditions for correctly determining the mechanism of thermal degradation. The utility of TG–FTIR in the study of APIs can be demonstrated by the example of naproxen ((+)-(
S)-2-(6-methoxynaphthalen-2-yl)-propionic acid) and ketoprofen ((
RS)-2-(3-benzoyl phenyl)-propionic acid) [
29].
TG and DSC studies revealed differences in the thermal degradation of naproxen in nitrogen and air. In nitrogen, naproxen degrades with complete mass loss in one stage, in the temperature range of 154–305 °C, without forming any residue. In air, mass loss was found in two stages; the first stage was associated with 97% mass loss in the temperature range of 153–366 °C. The mass loss in the second stage was 1.5% and was due to afterburning of the coked residue. A sharp endothermic DSC peak in nitrogen and air confirmed the melting of naproxen at 153.5 °C. Subsequent endothermic and exothermic peaks reflected naproxen degradation, especially in the air. In turn, TG–FTIR analysis showed the presence of 2-methoxynaphthalene and propionic acid among the volatile degradation products. Characteristic FTIR bands indicating the presence of 2-methoxynaphthalene were found at 3100–2900 cm–1 and 1250–1000 cm–1, while bands characteristic of propionic acid were observed at 1780–1750 cm–1. Unlike naproxen, ketoprofen shows a complete mass loss in one step, in the temperature range of 164–329 °C in nitrogen and 156–338 °C in air. The sharp endothermic DSC peak was attributed to the melting of ketoprofen at 93.3 °C, while the second endothermic peak likely reflected evaporation. Evaporation of melted ketoprofen rather than decomposition was also confirmed by the absence of a coked residue (TG curve) and volatile degradation products (TG–FTIR).
Studies conducted showed that ketoprofen evaporates after melting without undergoing any thermal degradation. This was also confirmed using isothermal TG carried out at 210 °C in nitrogen. Under these conditions, both ketoprofen and naproxen evaporate from the melted sample without degradation. In contrast to ketoprofen, naproxen undergoes thermal degradation during dynamic heating, especially in the air. This was confirmed with the volatile degradation products and the coked-out decomposition residue.
Another example is the decomposition of oxytetracycline hydrochloride ((4
S,4a
R,5
S,5a
R,6
S,12a
S)-4-(dimethylamino)-3,5,6,10,11,12a-hexahydroxy-6-methyl-1,12-dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide hydrochloride) [
30]. TG measurements in the air indicated three stages of mass loss in the temperature ranges of 25–128 °C, 128–339 °C and 339–644 °C, respectively. This was confirmed by the DTA curve. The endothermic peak at 52 °C reflected the dehydration and release of hydrochloride during the first mass loss. A sharp exothermic DTA peak at 215 °C confirmed oxidative degradation in the second stage, while two exothermic peaks at 531 and 659 °C corresponded to the combustion of the coked residue in the last stage. TG–FTIR indicated that water and hydrochloride appear in the first stage of mass loss, while isocyanic acid, carbon dioxide, dimethylamine and ammonia were identified in addition to water and hydrochloride in the second stage. At approx. 510 °C, the final decomposition revealed the presence of methane. The TG, DTA and TG–FTIR studies enabled the development of an indicative mechanism of the thermal decomposition of oxytetracycline hydrochloride.
Studies have shown that, regardless of the identification of volatile degradation products, data on solid degradation products are also required to develop an accurate mechanism of the thermal degradation of APIs. Such a study was performed by determining the mechanism of thermal degradation of metoprolol tartrate (1-[4-(2-methoxy ethyl)-phenoxy]-3-(propan-2-ylamino)-propan-2-ol tartrate) [
31]. TG and DTA showed that API degradation occurred with two or three mass losses depending on the atmosphere in which the degradation was carried out. TG in nitrogen indicated two consecutive mass losses, 22% in the 155–232 °C temperature range and 77% in the 232–653 °C range. The degradation processes were confirmed by two endothermic DTA peaks in these temperature ranges. In the air, similar results were obtained; the mass losses and temperature ranges for three consecutive stages were as follows: 22, 73 and 6% in the 153–229, 229–445 and 445–1000 °C ranges, respectively. The degradation processes were confirmed by endo- and exothermic DTA peaks. The degradation was preceded by a sharp endothermic peak at 123.3 °C, associated with melting metoprolol tartrate.
The TG–FTIR coupled system was used to identify gaseous degradation products formed during thermal decomposition of metoprolol tartrate. The interpretation of the obtained data is shown in
Figure 4. FTIR spectra of volatile degradation products were compared with reference spectra obtained from the NIST and Nicolet TGA Vapor Phase databases. Based on this methodology, TG–FTIR in nitrogen confirmed the presence of carbon monoxide, carbon dioxide and water in the first stage of mass loss. This indicates the degradation of tartaric acid. The theoretical mass loss associated with the degradation of this acid is consistent with the mass loss in the first stage of degradation. In the second stage of mass loss, dimethyl ether, 1-ethoxy-4-methylbenzene, isopropyl isocyanate, carbon dioxide and ammonia were identified. In addition, HPLC/MS analysis of the solid thermal decomposition products obtained by heating metoprolol tartrate to 290 °C suggests that intramolecular interaction in the liquid phase leads to the formation of molecules with higher mass than metoprolol. Combining all the results, it was found that the heated substance melts, followed by the decomposition of tartaric acid, the degradation of metoprolol with the formation of dimers and the destruction of the resulting structures with the formation of a coked residue that burns at high temperatures.
The mechanism of thermal degradation of tenofovir disoproxil fumarate (bis {[(isopropoxycarbonyl)-oxy]methyl} ({[(2
R)-1-(6-amino-9
H-purin-9-yl)-2propanyl]-oxy} methyl) phosphonate fumarate) was also investigated, using TG–FTIR to identify volatile degradation products and HPLC and LC/MS to study solid residues [
22]. Endothermic DSC peaks indicated that the substance under study melts in nitrogen at 110.9 °C, while it melts in the air at 110.7 °C. Melting is followed by decomposition, and the second endothermic DSC peak indicates thermal destruction as the main degradation pathway.
TG studies have shown that the decomposition of tenofovir disoproxil fumarate is accompanied by three stages of mass loss. They occur in the temperature ranges 138–195 °C, 195–415 °C and 415-approx. 800 °C, with mass losses of, respectively: 35%, 25% and 23% in nitrogen and 34%, 23% and 23% in air. Stage one can be characterized as a rapid degradation process, while stage two reflects slow degradation. The degradation process in this stage is complex, as indicated by several small DTG peaks. Stage three, on the other hand, is a very slow process.
Comprehensive studies realized using TG–FTIR (identification of volatile degradation products), HPLC and LC/MS (identification of solid degradation products) and quantum chemistry methods (prediction of the chemical structure of degradation products) made it possible to develop the mechanism of destruction of tenofovir disoproxil fumarate. It was shown that in both atmospheres, the mechanism of degradation in the first two stages of mass loss is very similar. The first stage begins with the degradation of the ester bond, followed by the degradation of the phosphate disoproxil group. This is the main degradation process in this stage, which completes the beginning of fumaric acid decomposition, simultaneously starting stage two. The main process in this stage is the degradation of the tenofovir grouping and partially the adenine grouping. In turn, in stage three, the adenine ring is degraded with the formation of a coked residue.
3.2. TG Coupled to Mass Spectrometry
Another coupled thermal technique used to study pharmaceuticals is TG–MS. TG–MS is distinguished by the fact that it allows not only the identification, but also the analysis of the chemical structure of volatile degradation products based on mass spectra (
m/
z ratio), while TG–FTIR provides only the identification of degradation products based on characteristic absorption bands associated with the presence of specific functional groups in the molecule. Numerous examples of the application of TG–MS, among others, in the study of nanomaterials, nanocomposites, polymers and other materials are presented in review papers [
14,
49].
A block diagram of the TG–FTIR equipment is shown in
Figure 5. As with TG–FTIR, in addition to the TG and MS devices, the most important component of this system is the interface that connects the outlet of the TG oven to the inlet of the ionization chamber of the mass spectrometer (MS) [
14,
15,
17]. The technical problem is that TG measurements are conducted at atmospheric pressure, while the MS has a high vacuum. Therefore, the connector must guarantee that the vacuum in the ionization chamber is maintained. The connector includes a capillary tube with the appropriate length and inner diameter. Through this capillary tube, volatile degradation products are transferred from the TG furnace to the MS ionization chamber, into which they are sucked by the pressure difference prevailing in the capillary tube and the ionization chamber. As in the case of TG–FTIR, the capillary tube is maintained at a certain temperature, which prevents condensation of volatile degradation products. The carrier gas is most often helium, but in some types of MS, it can also be air.
Based on the literature data, it can be concluded that coupled TG–MS systems are relatively rarely used to study pharmaceuticals. Only a few examples can be found, with the equipment used for exploring and the measurement conditions varying greatly. This is illustrated in
Table 3.
The data compiled in
Table 3 indicates that, as in the case of TG–FTIR, equipment from TA Instruments, model SDT 2960 DSC-TGA, and a mass spectrometer from Pfeiffer Vacuum, model Balzers ThermoStar Quadrupole Mass Spectrometry, were most commonly used for API studies. The authors of the cited publications, however, rarely provided detailed data on how the two instruments were combined and on MS analysis conditions. They did, however, provide data on TG analysis conditions. The most common sample masses used were 5–10 mg [
42,
47] and 15-20 mg [
34]. In one case, the sample mass was as high as 161.5 mg [
52]. Samples in open α-alumina sample holders [
42,
47] or platinum crucibles [
34] were heated from ambient temperature to 300 °C [
53], 400 °C [
47,
52], 500 °C [
34] or 800 °C [
42]; at heating rates of 5 °C/min [
34,
44,
47], 10 °C/min [
42,
47,
52,
53] or 15 °C/min [
47]; in helium [
44], argon [
47,
52] or nitrogen [
34,
53]; and at flow rates of 16 mL/min [
53], 20 mL/min [
34,
47], 100 mL/min [
52] or 10 L/h [
44].
The literature also describes a dual-coupled system that allows simultaneous analysis of TG, DSC, MS and FTIR in real time [
57]. This system includes an apparatus for TG–DSC (STA 449 Jupiter, Netzsch), quadrupole mass spectrometer (OMS 403C Aëolos, Netzsch) and FTIR spectrometer (Tensor 27, Bruker). The TG–DSC device is connected to both spectrometers via a transfer line, through which volatile degradation products are simultaneously and continuously delivered to the QMS and FTIR devices. Both QMS and FTIR allow analysis of gaseous degradation products, with the difference that QMS provides qualitative and quantitative composition information, while FTIR allows identification of functional groups along with information on the aliphatic or aromatic nature of the gaseous products. By exploring natural polymers with complex chemical compositions isolated from soils that differ in chemical composition, the suitability of the TG–DSC–QMS–FTIR device for studying the chemical properties and thermal stability of fulvic and humic acids was tested.
Examples of the application of TG–MS in the study of pharmaceuticals are shown in
Table 4. An interesting solution is the use of atmospheric pressure photoionization (APPI) for the analysis of acetylsalicylic acid tablets from different manufacturers [
54]. The mass spectra obtained made it possible to detect the active ingredient in all tablets under study and to identify the tablet manufacturers. The data obtained showed that the developed new analytical technologies could be potentially useful in the quality control of pharmaceutical preparations and the identification of adulterated products.
In turn, the thermal decomposition of lornoxicam ((3
E)-6-chloro-3-[hydroxy (pyridin-2-ylamino)methylene]-2-methyl-2,3-dihydro-4
H-thieno [2,3-
e] [
1,
2] thiazin-4-one 1,1-dioxide) can serve as an example for the analysis of volatile and solid degradation products formed both in inert nitrogen and an oxidizing air atmosphere [
42]. Lornoxicam melts at 225–230 °C with simultaneous decomposition, which proceeds in two stages with significant mass losses. The first stage is accompanied by a 63–64% mass loss in the temperature range of 205–360 °C, regardless of the type of atmosphere (nitrogen, air). The mass loss in stage two is strongly influenced by the atmosphere. In nitrogen, there is slow pyrolysis in the temperature range of 360–800 °C, resulting in a small mass loss (15%). In the air, on the other hand, in a narrower temperature range (360–680 °C), oxidative degradation occurs, accompanied by a greater mass loss (39%). The exothermic DSC peak in this stage confirms the oxidation of the degradation products formed in stage one.
Volatile degradation products were analyzed using coupled DSC/TG–FTIR and TG–MS systems. Carbon dioxide, carbonyl sulfide, sulfur dioxide and hydrogen cyanide were found to be released in both air and nitrogen. In contrast, at higher temperatures, the qualitative and quantitative composition of volatile degradation products was strongly influenced by the atmosphere. Carbon dioxide and sulfur dioxide were detected in nitrogen, while carbon monoxide, carbon dioxide, nitrous oxide, carbonyl sulfide and sulfur dioxide were detected in air. Solid degradation products were also studied using LC/MS/MS. These were obtained by heating lornoxicam in a DSC/TG device under isothermal conditions at temperatures of 180, 220 and 235 °C. Three degradation products with complex chemical structures were identified from the mass spectra, two at 220°C—[M+H]+ m/z = 336, MS/MS 121 and [M+H]+ m/z = 356, MS/MS 148, 121, and the third at 235 °C—[M+H]+ m/z = 310, MS/MS 216, 95.
The effects of the chemical structure and geometric configuration of citric acid and aconitic acid isomers on the stability of decomposition products and the direction of thermal transformation were also studied using TG–FTIR and TG–MS coupled systems [
47]. TG and DSC showed that cis-aconitic acid showed the lowest stability, while citric and trans-aconitic acids showed similar stability, much higher than the stability of cis-aconitic acid. This indicates that the configurational isomerism of aconitic acid has a significant effect on its thermal decomposition. The study also showed that citric and trans-aconitic acids can undergo thermal transformation (dehydration) directly to trans-aconitic anhydride. This transformation suggests that the geometrical configuration has a strong influence on the degradation pathway of aconitic acid isomers. Trans-aconitic anhydride, in turn, undergoes decarboxylation to itaconic anhydride, citraconic anhydride or a mixture of the two.
3.3. TG Coupled to GC/MS
TG–GC/MS is another coupled thermal technique classified in the group of non-continuous simultaneous techniques, i.e., it involves the studying of the same sample using two or more coupled measurement techniques when the collection of material to be explored for the other technique is not continuous. For this reason, measurements via TG–GC/MS do not take place in real time.
A block diagram of the equipment for TG–GC/MS is shown in
Figure 6. Volatile degradation products that are released from the sample during heating are properly collected over specific temperature ranges in an appropriate manner and then fed into GC/MS [
14,
15]. The main advantage of the coupled TG–GC/MS system is that it provides information on the chemical structure of volatile degradation products, while TG–FTIR only allows the identification of volatile degradation products.
There are few examples in the literature of the application of coupled TG–GC/MS systems in the study of pharmaceuticals. One of them presents the results of zidovudine (azidothymidine, 1-[(2
R,4
S,5
S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methyl pyrimidine-2,4-dione) [
58]. TG, DTG and DSC studies under a nitrogen atmosphere showed that the thermal decomposition of zidovudine occurs in three stages, for which mass losses and temperature ranges are as follows: 51.8%, 153–249 °C; 20.3%, 249–357 °C; and 28.2%, 360–650 °C. Degradation is preceded by the melting of the substance at 126.6 °C.
Volatile degradation products were obtained by heating zidovudine in the temperature range of 30–900 °C in a dynamic helium atmosphere. They were adsorbed onto Tenax 60/80 mesh porous polymer adsorbent and cooled to dry-ice temperature. After desorption at 300 °C, the volatiles were separated on a gas chromatograph coupled to a mass spectrometer under a helium atmosphere. Identifying the chemical structure of the volatile products, the mass spectra of the GC-evolved compounds were compared with standards from the National Institute of Standards (NIST) database. The presence of 2-furanomethanol and furan was found. In turn, using elemental analysis (C, H and N), IR, PXRD and DSC, it was suggested that the solid decomposition product of zidovudine in the first decomposition step is thymine. Such a mechanism confirms the presence of 2-furanomethanol among the volatile degradation products. In the second stage, thymine is degraded to form an intermediate product with fragments of the thymine structure. In the third stage, the coked residue burns.
Reliable analysis of volatile degradation products can also be performed using coupled systems consisting of a pyrolyzer and GC/MS (Pyr-GC/MS). An example is the study of the thermal degradation of simvastatin ((1
S,3
R,7
S,8
S,8a
R)-8-{2-[(2
R,4
R)- 4-hydroxy-6-oxotetrahydro-2
H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate) [
59]. Successive samples corresponding to single crystals of simvastatin were placed in a platinum crucible and pyrolyzed under isothermal conditions at temperatures of 200, 250, 300, 400 and 550 °C. Volatile products obtained at the specified temperature were introduced into GC/MS using helium as a carrier gas. Fragmentation was carried out with electron ionization, and the mass spectrometer was operated in SCAN mode, scanning the
m/
z range of 50–550. Data obtained from Pyr-GC/MS analysis indicated a good correlation between pyrolysis mass losses and thermal decomposition by TG. The identification of new compounds based on the signals in the mass spectra (peaks at
m/
z 284 and 207) formed during the first stage of decomposition indicates the complexity of the degradation process and explains the difficulty in determining the sequence of reactions during the isothermal decomposition of simvastatin.
Coupled Pyr-GC/MS systems were further used to study the thermal degradation processes of tacrolimus [
60], fluconazole [
61], efavirenz [
62] and raw medicinal plant material [
63]. However, it should be noted that pyrolysis is not a thermal analysis technique. In this method, no physical properties of the samples are recorded, and thermal decomposition does not take place under conditions of programmed temperature changes. Therefore, only a brief description of this technique is given, without further discussion of the use of Pyr-GC/MS in the study of pharmaceuticals.