2.3.1. Thermal Analysis
A DSC study (Figures S1 and S3
) it was carried out by selecting mixtures of drug-excipients in a 1:1 ratio (w/w). The DSC equipment was calibrated using indium and high purity zinc as a reference material to standardize temperature and heat flux signals. The samples of approximately 3 mg were subjected to programmed heating under dynamic nitrogen gas purge according to previously explained conditions. First, it was necessary to understand the behaviour of each API and excipients (Figure S1
Loperamide HCl crystallizes fewer than three different crystalline forms: an anhydrous polymorphic form I representing the stable polymorph of isometric crystals and the metastable form (melting point approximately 224 °C), an anhydrous polymorphic form II (melting point of approximately 218 °C); these are needles [38
] and a tetrahydrated form, whose melting point is around 190 °C [41
The DSC-thermogram of the original loperamide HCl powder selected in this study exhibits a single endothermic peak located at Tonset = 229.48 °C (ΔHF = 1480.48 J/g), which indicates fusion, is a typical compound event crystalline anhydrous, in this case corresponding to polymorphic form I, followed by an endothermic decomposition process at temperatures above the melting point (Tonset = 259.65 °C). Mannitol has a broad endothermic peak corresponding to the fusion at Tonset = 165.81 °C and the area under the peak reveals an enthalpy of fusion at 286.07 J/g. Mannitol used in this investigation was its form II (Tonset = 165.81 °C), and also the compactability of this polymorph is higher compared to the other two crystalline forms (form I and form III).
New experimental conditions were used to study HPMC, and a cycle of 0 to 200 °C was designed at a heating rate of 200 °C/min, which allowed for observing that the Tg of HPMC occurs at 178 °C. The DSC-anise and DSC-sodium starch glycolate (type A) (Explotab®)
exhibited a single endothermic event located at 166.29 and 165.83 °C, respectively. Magnesium stearate has several peaks at 62.57 and 92.73 °C due to the loss of surface water and close to 112 °C due to the fusion of magnesium palmitate, since in its composition stearic acid and palmitic acid appear (this impurity frequently occurs in commercial lots of magnesium stearate), followed by degradation at 178 °C. Calcium hydrogen phosphate (Emcompress®
) has two endothermic events, one around 110 °C corresponding to the onset of the evaporation of the hydration water and another around 135 °C that can be associated with a phase transition of the crystal. Landin et al. [43
] claimed that dehydration takes place in two steps and that it occurs according to particle size. Menthol emanates in two forms, L-menthol and dL-menthol, with different polymorphism α, β, γ and δ for L-menthol and polymorphs α, β γ for dL-menthol. The melting temperatures for L-menthol are 42.45, 36.85, 35.55 and 35.15 °C, and moreover for dL-menthol they are 32, 27.55 and 22.75 °C, respectively. DSC-menthol given a wide endotherm, so it was necessary to design a new heat–cold cycle, at high heating and cooling rates (100 °C/min). After the first heating cycle, the sample cooled at a high speed, which means that it cannot be completely crystallized to a temperature of −60 °C. In the second heating cycle, a glass transition was observed at approximately −27 °C followed by a fusion that begins around 30 °C.
Lastly, the literature indicates that monosodium cyclamate exists in two pseudopolymorphic forms [44
], such as sodium cyclamate dihydrate and anhydrous sodium cyclamate. In this study hydrated form of sodium cyclamate presented an endothermic signal at 154.8 °C in the thermogram, with a shoulder at 55 °C, referring to the dehydration process. Dehydration of sodium cyclamate is a process that occurs in multiple steps spontaneously at room temperature followed by a process of decomposition around 190–200 °C due to a dimerization that leads to the formation of N, N’-dicyclohexylsulfamide and sodium sulfate. The interactions between the mixtures in these calorimetric studies are deduced by the appearance or disappearance of peaks, peak jumps especially in that associated with fusion and/or variations in enthalpy values it is not necessary these may be greater or lesser), interchangeably, they may occur changes in the shape of the peak [45
] although it should be considered that some peak enlargements are due to a decrease in the purity or crystallinity of each component in the mixture.
Next, the results of the binary mixtures of the API with each of the excipients used are described (Figure 2
) to maximize the possibility of observing and producing interaction. The curves exhibit a characteristic behaviour for each compound. Figure 2
A,B represent the DSC of loperamide HCl, mannitol or magnesium stearate and their physical mixtures. The jump at lower temperatures of the endothermic event corresponding to the fusion of the API, from 229.48 to 185.73 °C and 198.75 °C, respectively, can be attributed to some solid–solid interaction or a reduction in individual purity but it does not necessarily mean incompatibility.
C–E corresponds to the physical mixture with HPMC, anise and Explotab®
; in all these cases, the fusion endotherm of the excipient has disappeared. This result has to be contrasted with the IR and SEM studies to reach a correct conclusion; that is, with these calorimetric results, no explanation can be definitive, one might think that HPMC degrades at 210 °C, which would produce a masking of the drug’s fusion endotherm in this physical mixture. These results have also been found for other drugs such as atovacone [46
] or to the complete solubility of the drug in the excipient, which melted at a lower temperature than the drug [47
F,G present the results corresponding to the physical mixture with sodium cyclamate and Emcompress®
, a change in the melting event matching to the active substance is observed, much more perceptible in the case of sodium cyclamate, for Emcompress®
occurs a jump to slightly lower temperatures of the endothermic event, but unlike the mannitol and magnesium stearate, the peak has a lower melting area, which clearly indicates that the crystallization water of calcium phosphate hydrogen partially dissolves the drug and the basic environment could contribute to this. This was verified by a new study with a second heating, it showed a broad melting peak corresponding to the drug changing at a lower temperature with a slight change in associated enthalpy. There are many active ingredients that are incompatible with this excipient for example famotidine [48
], quinapril [49
] or metronidazole [50
To conclude, Figure 2
H represents DSC of loperamide HCl, menthol and physical mixture. The slight reduction in the melting temperature of the drug can represent a physical interaction between both elements without indicating an incompatibility, because the average enthalpy value for the mixture is statistically equal to that found for loperamide HCl alone. More significant changes in enthalpy values would indicate a possible chemical incompatibility between them, which could lead to the partial or total loss of the pharmacological activity of the future medication.
The use of spectroscopic methods such as FT-IR in preformulation has contributed significantly to the early prediction and characterisation of possible physical or chemical interactions between the drug and excipient and to assist in the rationalized selection of the most appropriate excipients in the design of dosage forms [37
]. In Figure S2
are represented the IR lectures of loperamide HCl and mannitol, calcium hydrogen phosphate dihydrate, sodium starch glycolate, magnesium stearate, sodium cyclamate, menthol, anise extract and HPMC, respectively. The IR spectrum of loperamide HCl (Figure S2
) revealed characteristic absorption peaks like those previously published [52
], ensuring the presence of certain functional groups. A very broad peak was obtained around 3200 cm−1
, indicating the presence of an interchangeable proton stretch (-OH). At around 2900 cm−1
, new peaks appear, indicating the presence of saturated carbons confirming the presence of the –CH group. Below 2000 cm−1
, which is the region of the fingerprint, many characteristic peaks of different functional groups of the molecule are observed, such as the -CO (1475 cm−1
), -R-Cl (1037 cm−1
), and a characteristic area between 770 and 735 cm−1
for aromatic hydrocarbons. The infrared of the excipients selected in the preparation of the dispersible tablets are detailed in Figure S2
and in Table 2
their main absorption peaks are summarized [47
After making an accurate comparison of the infrared of the physical mixtures API + excipients and those obtained for the individual raw materials, it has been found that the infrared of the excipients, mannitol, sodium cyclamate and Emcompress®
showed the major differences with a clear enlargement of the highest region, possibly due to an overlap between the drug and excipient [53
]. This region has been highlighted where such divergences appeared in the spectral characteristics with respect to each individual spectrum, to differentiate it in greater detail in Figure 3
summarizes the values of the most prominent peaks in the region indicated (green rectangle in Figure 3
). The 3402.8, 3419.72 and 3736.9 cm−1
peaks of each of these three excipients have a value greater than 3235.93 cm−1
of loperamide HCl. One possible reason could be the formation of hydrogen bonds with the drug [54
On the other hand, in the case of the sweetener, it can be explained by the possible existence of interaction between the -NH group of sodium cyclamate that interacts with the -CH3 group of loperamide HCl. From these values, it follows that it was the physical mixture with sodium cyclamate and Emcompress®, in the calorimetric studies, which showed more significant changes in the event of fusion of the API, and of minor importance for the mannitol, which only meant a shift to lower temperatures than fusion.
2.3.3. SEM Studies
This technique consists of having an electron beam influence the sample. This bombardment of electrons causes the appearance of different signals that, captured with suitable detectors, provide us with information about the nature of the sample. In this analysis, a secondary electron signal (SE) was used that provided an image of the surface morphology of the sample and a backscattered signal (BSE) that gave a qualitative image of areas with different average atomic number. In order to ensure particle maintaining desired and physical characteristics during the compression manufacturing process, a SEM test was done. This technique also provided a qualitative assessment of size, shape, morphology, porosity, size distribution, crystal form, and consistency of powders or compressed dosage forms [55
]. The information proportionated by SEM could guide us to ensure the defined ODT quality characterization.
confirm represented SEM studies of loperamide HCl and the excipients selected in the final ODT (formulas n°14 and n°15). Figure S3
shows the irregular crystals of the drug with regular flat surfaces and sharp edges [56
]. Mannitol appears as orthorhombic needles when it crystallizes from alcohol, and anhydrous dibasic calcium phosphate appears as a white powder in the form of triclinic crystals. Explotab®
is shown as a hygroscopic powder in the form of irregular, ovoid or pear-shaped granules, size 30–100 mm, or even rounded. Magnesium stearate and sodium cyclamate are discovered as very fine powders, of a light white colour and with very irregular edges. Menthol is a powder of acicular or hexagonal crystals, in which its observation is difficult because the crystalline form can change over time due to the sublimation that takes place during the period of observation in the microscope. Figure S3
shows the round shape and the smooth and homogeneous surface of the HPMC; this will undoubtedly allow excellent dispersion and will influence the drug release modifier. Finally, anise extract is revealed as a very heterogeneous powder of soft shapes and with very different sizes.
SEM studies have also been carried out with the drug–excipient physical mixtures but have not produced any revealing data. Nevertheless, SEM studies of cross-section ODT (formulas n°14 and n°15) (Figure 4
) offered revealing results. Both are presented using a 50 and 200 µm resolution. In both cases, a well-compacted mixture is seen on whose surface large spherical particles corresponding to the sodium starch glycolate perfectly dispersed inside are visible [47