Thermal and Spectral Characterization of a Binary Mixture of Medazepam and Citric Acid: Eutectic Reaction and Solubility Studies

: Medazepam, citric acid and their binary mixtures were studied using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) for thermal and structural properties. The DSC data show a simple eutectic peak at 370 K. To determine the exact mole fraction at which the eutectic occurs, Tamman’s triangle was used. The obtained results show that the eutectic mixture appears at a molar fraction of medazepam of approximately 0.85. The excess thermodynamic functions G E , S E and µ E were calculated, and the results were interpreted to evaluate the interactions that occur between the components of the mixture. The FTIR results were used to conﬁrm the eutectic formation. Solubility tests in deionized water show a 40-times increase in the medazepam solubility from the eutectic mixture, from 0.73 µ g/mL to 28.61 µ g/mL. However, further tests showed that the acidic character of the sample was the main factor responsible for this increase.


Introduction
Medazepam (7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine, C 16 H 15 ClN 2 ) is a benzodiazepine with anxiolytic, muscle relaxant and anticonvulsant actions [1].This drug relieves the feeling of worry, restores emotional calm and has a stabilizing effect on the autonomic nervous system.Medazepam is used in neurosis, psychopathy accompanied by excitement, stress, increased irritability, insomnia and the functional neurosis of the cardiovascular system.Such a benzodiazepine with a weak or absent sedative-hypnotic character is also called a "daytime tranquilizer".
Medazepam is a drug that is practically insoluble in water but easily soluble in alcohol, chloroform and ether [3].To improve the therapeutic effect and for rapid absorption in the human body, its solubility in water must be increased.
The structural formulas of these compounds are presented in Figure 1.
Thermo 2023, 3, FOR PEER REVIEW 2 components [5,6].A eutectic system is formed only when there is a specific ratio between the components [7].
(a) (b) Eutectic systems usually have useful properties that single components do not, which leads to applications in various fields.The intermolecular interactions that occur in a eutectic system are short-range, weak, and noncovalent interactions [8].
There are three possible cases that can be encountered [9]:.One of the major problems faced by the pharmaceutical industry in the development of new drugs is the low solubility and dissolution rate of the active pharmaceutical ingredient [4].
In the literature, there are several ways to improve the solubility of the active principles, such as eutectic formation, salts formation, pH changes, and cocrystal formation.
The eutectic system is a homogeneous solid mixture formed by two or more substances that melt at a lower temperature than the melting point of any of the individual components [5,6].A eutectic system is formed only when there is a specific ratio between the components [7].
Eutectic systems usually have useful properties that single components do not, which leads to applications in various fields.The intermolecular interactions that occur in a eutectic system are short-range, weak, and noncovalent interactions [8].
There are three possible cases that can be encountered [9].The first one is when a simple eutectic is formed, in which case the physical mixture of eutectic composition may have different properties compared to those of the respective melt.
The second case is when an intermediate compound is formed.Its identity and properties must be determined, since, after ingestion, it may or may not break down into the original compounds, or may as such have different pharmaceutical properties from those of the original compounds.
The third one is when a solid solution is formed.The solid solution is formed between a poorly soluble active principle and another compound, and then the solubility of the active principle can be improved.
There are several examples of increasing the solubility of active pharmaceutical ingredients or the dissolution rate in the literature using eutectic formation, such as caffeine with meloxicam, aceclofenac and flurbiprofen [10]; efavirenz and tenofovir disoproxil fumarate [11]; simvastatin and aspirin [12]; etodolac with paracetamol or propranolol hydrochloride [13]; and levetiracetam with ibuprofen, naproxen, ketoprofen or flurbiprofen [14].
Another method for increasing solubility is salt formation.This occurs through a reaction between an acid and a base, which requires an ionizable center in the active pharmaceutical ingredient considered.These salts are compounds formed via the complete transfer of protons from one component to another.This method is limited because there are a small number of non-toxic, pharmaceutically acceptable acids and bases [15].
Another way to increase the solubility is by changing the pH.Changing the pH can solubilize some insoluble substances.For example, local anesthetics can be solubilized at an acidic pH, and barbiturate derivatives ad aspirin can be solubilized at an alkaline pH, obtaining the corresponding salts [16][17][18][19].
An increase in solubility can also be achieved through cocrystal formation.Cocrystals are solid, crystalline substances composed of two or more molecules in the same crystalline network [20].In cocrystals, the two components active pharmaceutical ingredient and excipient, are bound together via noncovalent interactions, namely hydrogen bonds, π−π overlaps or Van der Waals forces.They can be obtained from non-ionizable active pharmaceutical ingredients or from complex formulations.Cocrystals are recognized for their stability in the solid state, but if they have a higher solubility than the active pharmaceutical ingredient during dissolution, disproportionation occurs and stability is affected [21][22][23].

Mixture Preparation
The mixtures were obtained through mechanosynthesis: mixtures of a selected molar fraction of medazepam and citric acid were mixed and ground for 5 to 10 min at room temperature, using a mortar and pestle, in order to achieve complete homogenization.

DSC
Medazepam, citric acid and their binary mixtures of different compositions were analyzed using DSC, and the corresponding melting temperatures and enthalpies were determined.The DSC parameters were the heating rate (10 degrees/min), cooling speed (50 degrees/min), default temperature range (293.15-582.3)K and inert atmosphere (argon 20 mL/min).The device used, the Perkin Elmer Diamond DSC (Waltham, MA, USA, 2008), was calibrated with pure indium, tin and naphthalene for temperature and enthalpy.Weighing of 1-10 mg samples was carried out with the Partner XA balance (Radwag, Poland, model XA 60/220, 2014) with an accuracy of 10 µg in aluminum crucibles with lids.
The Peak Analyzer function in the Origin software combined with the Gaussian function was used for the DSC peaks' deconvolution.

FTIR
Fourier transform infrared spectra were recorded with an attenuated total reflectance (ATR) reading method, with a ZnSe crystal.Transmittance was measured with a Perkin Elmer Frontier MIR/FIR instrument (Waltham, MA, USA, 2015) in the wavelength range from 650 cm −1 to 4000 cm −1 with a resolution 1 cm −1 .

Solubility Tests
Solubility tests for citric acid, medazepam and their eutectic mixture in deionized water were run using a rotating mixer at (296 ± 1.5) K.The rotating mixer was acquired from Heidolph, model Reax 2, and has the production year 2014.The UV-Vis Spectrophotometer Perkin Elmer Lambda 45 (Waltham, MA, USA, 2014) was used for UV-Vis spectra determination.The device used has a resolution of 1 nm and the set up range was (200-700) nm range.For each spectrum, deionized water was used as blank.The device used in deionized water production was made by GLF, model 2002, and has the production year 2007.
The DSC curves of the pure compounds and the binary mixtures are shown in Figure 2. The maximum temperature for both eutectic and excess was taken into account because the two DSC peaks are not well separated.For medazepam mole fractions of 0.9003 and 0.9519 a peak deconvolution was required.The Peak Analyzer function in the Origin software combined with the Gaussian function was used for the peak deconvolution.The results are presented in Figure 3 and Table 1.
The DSC data of citric acid show an endothermic peak at 432.7 K (∆H = 219.3J•g −1 ), associated with melting, accompanied by a broad endothermic peak, associated with decomposition.For medazepam, the DSC data show a single endothermic peak at 375.3 K (∆H = 97.7 J•g −1 ), associated with melting.
The data DSC obtained for the medazepam-citric acid binary mixtures are shown in Table 1.From Figure 2, it can be seen that the formation of the eutectic always occurs at a lower temperature than that of the single components, accompanied by the melting of the excess component.Origin software combined with the Gaussian function was used for the peak deconvolution.The results are presented in Figure 3 and Table 1.Origin software combined with the Gaussian function was used for the peak deconvolution.The results are presented in Figure 3 and Table 1.In Figure 2, the DSC data show a single melting peak for citric acid.When medazepam is added to the mixture, two peaks appear: the first is associated with the formation of the eutectic, and the second is associated with the melting of the excess component-citric acid.When the mole fraction of medazepam continues to increase, the ratio of the peaks (eutectic to citric acid) shifts in favor of the eutectic.In the range of mole fractions of medazepam (0.30-0.85), a single peak corresponding to the eutectic can be observed.When the mole fraction of medazepam continues to increase (x Medazepam = 0.90; x Medazepam = 0.95), two peaks appear that are not well separated: the eutectic and the excess component, medazepam.This weak separation is also due to the melting points of the eutectic (370 K) and medazepam (375.3K), which are very close.Again, for the pure component, at x Medazepam = 1, a single peak corresponding to its melting appears.All the characteristics presented above show that the system exhibits all the characteristics of a eutectic:

•
Single compounds that have a lower melting temperature;

•
The eutectic peak, which has a lower temperature than that of the single compounds;

•
The increase in the enthalpy value of the eutectic until the eutectic point is reached, associated with the decrease in the enthalpy value of the excess component.
The only way to determine exactly the eutectic composition is by drawing Tamman's triangle [24].This is a plot of the eutectic peak enthalpy versus he mole fraction (Figure 4).To build this graph, in the case of the molar fractions of 0.90 and 0.95, the data obtained from the deconvolution of the peaks were used.A eutectic system is represented by a triangle in the Tamman diagram.As can be seen in Figure 4, the eutectic enthalpy value increases linearly (y = 60.796x,R 2 = 0.9643) until it reaches the eutectic point (x Medazepam = 0.8565), after which it decreases linearly (y = −400.45x+ 395.05,R 2 = 0.9983).The points of intersection of the mole fraction axis with Tamman's triangle delineate the mole fractions at which solid solutions can occur [25].As seen in Figure 4, solid solutions can be formed at the extremities of the phase diagram above x Medazepam = 0.9865.Figure 5 shows the phase diagram of the considered binary system.A simple eutectic point constituted by the first endothermic peak, placed approximately at 370 K, is present for all compositions of the mixtures.In conclusion, it can be said that the binary system of medazepam and citric acid presents a eutectic at the molar fraction of medazepam XMedazepam = 0.85. Figure 5 shows the phase diagram of the considered binary system.A simple eutectic point constituted by the first endothermic peak, placed approximately at 370 K, is present for all compositions of the mixtures.In conclusion, it can be said that the binary system of medazepam and citric acid presents a eutectic at the molar fraction of medazepam X Medazepam = 0.85. Figure 5 shows the phase diagram of the considered binary system.A simple tic point constituted by the first endothermic peak, placed approximately at 37 present for all compositions of the mixtures.In conclusion, it can be said that the system of medazepam and citric acid presents a eutectic at the molar frac medazepam XMedazepam = 0.85.In Figure 5, the experimental phase diagram obtained from DSC data is sym using triangles (eutectic temperatures-Table 1, second column) and squares ( DSC peak temperatures-Table 1, fourth column).The ideal diagram, symbolized points, is obtained from the Schröder-Van Laar equation [26]: where xi is the mole fraction of component i at temperature T, γi is the activity coe of component i, Δ t Hi is the molar fusion enthalpy of component i, R is the gas co and Ti is the melting temperature of the single component.
As seen in Figure 5, the experimental data fit the ideal curve only in the meda mole fraction range of 0.85-1.0.Otherwise, it shows a deviation from the ideal be In Figure 5, the experimental phase diagram obtained from DSC data is symbolized using triangles (eutectic temperatures-Table 1, second column) and squares (second DSC peak temperatures-Table 1, fourth column).The ideal diagram, symbolized using points, is obtained from the Schröder-Van Laar equation [26]: where x i is the mole fraction of component i at temperature T, γ i is the activity coefficient of component i, ∆ t H i is the molar fusion enthalpy of component i, R is the gas constant, and T i is the melting temperature of the single component.As seen in Figure 5, the experimental data fit the ideal curve only in the medazepam mole fraction range of 0.85-1.0.Otherwise, it shows a deviation from the ideal behavior.Because of this deviation, it can be concluded that there are interactions between the two components over the entire mole fraction region framed by these two curves.
The thermodynamic excess functions (S E , G E and µ E ) can define the nature and type of interactions from a binary system as a deviation from ideality [27]: REVIEW 7 Because of this deviation, it can be concluded that there are interactions between the two components over the entire mole fraction region framed by these two curves.The thermodynamic excess functions (S E , G E and μ E ) can define the nature and type of interactions from a binary system as a deviation from ideality [27]: ) The values of the excess thermodynamic functions and activity coefficients were obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and Figure 6.
Table 2. Thermodynamic excess functions (S E , G E and μ E ) and calculated activity coefficients for the citric acid-medazepam mixture.

XMedazepam Ti(K) lnγ
Citric Acid Thermo 2023, 3, FOR PEER REVIEW 7 Because of this deviation, it can be concluded that there are interactions between the two components over the entire mole fraction region framed by these two curves.The thermodynamic excess functions (S E , G E and μ E ) can define the nature and type of interactions from a binary system as a deviation from ideality [27]: The values of the excess thermodynamic functions and activity coefficients were obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and Figure 6., G E and μ E ) and calculated activity coefficients for the citric acid-medazepam mixture.

XMedazepam Ti(K) lnγ
Citric Acid Thermo 2023, 3, FOR PEER REVIEW 7 Because of this deviation, it can be concluded that there are interactions between the two components over the entire mole fraction region framed by these two curves.The thermodynamic excess functions (S E , G E and μ E ) can define the nature and type of interactions from a binary system as a deviation from ideality [27]: The values of the excess thermodynamic functions and activity coefficients were obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and Figure 6., G E and μ E ) and calculated activity coefficients for the citric acid-medazepam mixture.

S E (J•mol
Thermo 2023, 3, FOR PEER REVIEW Because of this deviation, it can be concluded that there are interactions between components over the entire mole fraction region framed by these two curves. The thermodynamic excess functions (S E , G E and μ E ) can define the nature a of interactions from a binary system as a deviation from ideality [27]: The values of the excess thermodynamic functions and activity coefficien obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and Figu , G E and μ E ) and calculated activity coefficient citric acid-medazepam mixture.

S E (J•mol
Thermo 2023, 3, FOR PEER REVIEW 7 Because of this deviation, it can be concluded that there are interactions between the two components over the entire mole fraction region framed by these two curves.The thermodynamic excess functions (S E , G E and μ E ) can define the nature and type of interactions from a binary system as a deviation from ideality [27]: (2) The values of the excess thermodynamic functions and activity coefficients were obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and Figure 6.
Table 2. Thermodynamic excess functions (S E , G E and μ E ) and calculated activity coefficients for the citric acid-medazepam mixture.

XMedazepam Ti(K) lnγ
Citric Acid The values of the excess thermodynamic functions and activity coefficients were obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and Figure 6.
Table 2. Thermodynamic excess functions (S E , G E and µ E ) and calculated activity coefficients for the citric acid-medazepam mixture.

X Medazepam T i (K) lnγ
Citric Acid Because of this deviation, it can be concluded that there are interactions betw components over the entire mole fraction region framed by these two curves The thermodynamic excess functions (S E , G E and μ E ) can define the natu of interactions from a binary system as a deviation from ideality [27]: The values of the excess thermodynamic functions and activity coeff obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and   Table 2. Thermodynamic excess functions (S E , G E and μ E ) and calculated activity coef citric acid-medazepam mixture.

XMedazepam Ti(K) lnγ
Citric Acid  As can be seen in Table 2 and Figure 6, the Gibbs free energy values h mum in medazepam molar fraction xMedazepam = 0.20 and a minimum in xMe The excess entropy follows the same increase/decrease patterns as Gibbs fre in mirror form.
The types of interactions that occur between the components are determ Gibbs excess free energy.In Figure 6, in the whole range of mole fractions of m Because of this deviation, it can be concluded that there are in components over the entire mole fraction region framed by the The thermodynamic excess functions (S E , G E and μ E ) can of interactions from a binary system as a deviation from ideali The values of the excess thermodynamic functions and obtained by applying Equations ( 2)-( 4) and they are presented  As can be seen in Table 2 and Figure 6, the Gibbs free e mum in medazepam molar fraction xMedazepam = 0.20 and a mi The excess entropy follows the same increase/decrease pattern in mirror form.
The types of interactions that occur between the compon Gibbs excess free energy.In Figure 6, in the whole range of mo The values of the excess thermodynamic functions and activity coefficien obtained by applying Equations ( 2)-( 4) and they are presented in Table 2 and Figu Table 2. Thermodynamic excess functions (S E , G E and μ E ) and calculated activity coefficient citric acid-medazepam mixture.

XMedazepam Ti(K) lnγ
Citric Acid lnγ Medazepam  As can be seen in Table 2 and Figure 6, the Gibbs free energy values have mum in medazepam molar fraction xMedazepam = 0.20 and a minimum in xMedazepam The excess entropy follows the same increase/decrease patterns as Gibbs free ene in mirror form.

S E (J•mol
The types of interactions that occur between the components are determined Gibbs excess free energy.In Figure 6, in the whole range of mole fractions of meda As can be seen in Table 2 and Figure 6, the Gibbs free energy values have a maximum in medazepam molar fraction x Medazepam = 0.20 and a minimum in x Medazepam = 0.85.The excess entropy follows the same increase/decrease patterns as Gibbs free energy but in mirror form.
The types of interactions that occur between the components are determined by the Gibbs excess free energy.In Figure 6, in the whole range of mole fractions of medazepam, the Gibbs excess free energy has a positive value, which suggests the existence of weak interactions between different components and strong associations between molecules of the same kind [28].

FTIR
FTIR spectroscopy was used to study the interactions between the mixture components.The FTIR spectrum of medazepam shows small peaks at 3060 cm −1 and 3035 cm −1 corresponding to asymmetric and symmetric aromatic (C-H) stretching.Similarly, at 2943 cm −1 and 2859 cm −1 , the (C-H) stretch from (CH 2 ) appears.At 1573 cm −1 and 1555 cm −1 , one can observe the asymmetric stretching of the bond (CC) in the aromatic ring.The bands at 1338 cm −1 and 1321 cm −1 are specific to asymmetric and symmetric (C-N) stretching.The peak at 1178 cm −1 is attributed to the (C-C) stretch, and the one at 600 cm −1 to the (C-Cl) stretch.
The IR spectrum of citric acid has a sharp peak at 3494 cm −1 , attributed to the free (O-H) stretch and a broad peak at 3278 cm −1 attributed to the (O-H) bond.At 1743 cm −1 and 1693 cm −1 , symmetric and asymmetric stretching of (C=O) can be observed.Similarly, the (C-O) stretch can be seen at 1171 cm −1 and 1138 cm −1 .The (OH) bend occurs at 1426 cm −1 .These results are similar to those obtained in our previous work [29,30].
The spectrum of the eutectic mixture contains both citric acid and medazepam peaks with small deviations.The peaks originating from citric acid have the following shifts: the symmetric and asymmetric vibration (C=O) appears in the mixture at 1744 cm −1 and 1699 cm −1 , and the stretching (C-O) can be seen at 1176 cm −1 and 1140 cm −1 .The peaks originating from medazepam have the following shifts: the peak attributed to the stretch (C-C) appears at 1176 cm −1 and the stretch (C-Cl) at 599 cm −1 .
These deviations highlight intermolecular interactions between the two compounds, mainly hydrogen bonds between (O-H) of citric acid and (C-Cl) of medazepam.As can be seen in Figure 7, the spectrum of the mixture shows no new peaks, which suggests the absence of covalent or ionic interactions between the components, excluding the cocrystal formation, which also confirms the eutectic formation [10,31].
cm and 2859 cm , the (C-H) stretch from (CH2) appears.At 1573 cm and 1555 cm can observe the asymmetric stretching of the bond (CC) in the aromatic ring.The at 1338 cm −1 and 1321 cm −1 are specific to asymmetric and symmetric (C-N) stre The peak at 1178 cm −1 is attributed to the (C-C) stretch, and the one at 600 cm − (C-Cl) stretch.
The IR spectrum of citric acid has a sharp peak at 3494 cm −1 , attributed to (O-H) stretch and a broad peak at 3278 cm −1 attributed to the (O-H) bond.At 17 and 1693 cm −1 , symmetric and asymmetric stretching of (C=O) can be observed.Sim the (C-O) stretch can be seen at 1171 cm −1 and 1138 cm −1 .The (OH) bend occurs cm −1 .These results are similar to those obtained in our previous work [29,30].
The spectrum of the eutectic mixture contains both citric acid and medazepam with small deviations.The peaks originating from citric acid have the following the symmetric and asymmetric vibration (C=O) appears in the mixture at 1744 cm 1699 cm −1 , and the stretching (C-O) can be seen at 1176 cm −1 and 1140 cm −1 .Th originating from medazepam have the following shifts: the peak attributed to the (C-C) appears at 1176 cm −1 and the stretch (C-Cl) at 599 cm −1 .
These deviations highlight intermolecular interactions between the two comp mainly hydrogen bonds between (O-H) of citric acid and (C-Cl) of medazepam.As seen in Figure 7, the spectrum of the mixture shows no new peaks, which sugg absence of covalent or ionic interactions between the components, excluding the co formation, which also confirms the eutectic formation [10,31].

Solubility Tests
Solubility tests were carried out on medazepam and the eutectic mixture in deionized water (electrical conductivity of 0.3 µS•cm −1 , neutral pH).These were performed using the saturation-shake-flask method.The studies were run simultaneously to remove the influence of working conditions on the results.The concentration of medazepam was determined in its saturated solution.
The tested substance and deionized water were placed in glass flasks and then in a rotary shaker.The initial results showed that the equilibration time is about 60 min.Solubility tests were carried out for 90 min in triplicate.The solubility of medazepam did not increase with longer equilibration time.Undissolved medazepam was seen before and after reaching equilibrium [32].The solution was aliquoted, and a PVDF, 0.45 µm, 25 mm syringe filter (Tisch Scientific) was used for the solid-phase removal.
In order to determine the medazepam concentration, UV-Vis spectroscopy was used.In the first phase of the solubility studies, the citric acid and the medazepam spectra were determined.The medazepam spectrum presents two peaks at 453 nm and 237 nm, while citric acid presents one peak at 205 nm.To be sure that the citric acid spectrum did not interfere with the medazepam assessment, the 453 nm wavelength was chosen for the medazepam assay.The medazepam molar extinction coefficient was calculated for the chosen wavelength, 453 nm, and it was found to be approximately 16,000 mL•µg −1 •cm −1 .
The solubility can be affected by thermodynamic parameters such as the melting temperature depression and the heat of fusion [24,33].The solubility of the eutectic increases with the decrease in the values of the thermodynamic parameters compared with the ones from the pure compounds.Keeping in mind that the melting temperature and enthalpy of medazepam are ~375 K and 97.7 J•g −1 , while in the eutectic mixture, we have ~370 K and 55 J•g −1 , an increase in the medazepam solubility was expected from the eutectic mixture compared with the singular compound.
The solubility tests have shown a 0.73 µg/mL medazepam solubility in deionized water.For the medazepam from the eutectic mixture, the solubility was 28.61 µg/mL.Thus, the solubility of medazepam was increased approximately 40 times.
In order to see which medium parameter influences the solubility the most (the acidic character of the coformer/the eutectic formation), a solubility test was performed for medazepam in HCl 0.1 M. When the experiment was run using this medium, the entire quantity of medazepam was solubilized, surpassing the threshold of being practically insoluble to a soluble drug.Keeping in mind that the human stomach has a medium with low pH, the orally administrated drugs do not need any enhancements regarding the solubility aspects.However, these findings can apply easily to the parenteral, topical or suppository pharmaceutical forms.

Conclusions
DSC tests performed on medazepam, citric acid and their binary mixtures show a eutectic: a new peak in the DSC curves of the binary mixtures appearing at a lower melting point than that of the single substances, namely 370 K.The FTIR technique confirms the eutectic formation: there were no significant changes in the eutectic spectrum compared to single substances.The small changes that occurred are attributed to weak intermolecular interactions between the single compounds and weak hydrogen bonds.
Solubility tests were performed to verify the application of the medazepam and citric acid eutectic.The solubility of medazepam in water was significantly enhanced in the eutectic mixture.In parallel, medazepam solubility tests in 0.1 M hydrochloric acid were performed to see which conformer properties influence solubility more: acidic character or eutectic formation.Although the solubility of medazepam is more influenced by the acidic character of the conformer than by the eutectic, its solubility has been improved for its application in the pharmaceutical industry for parenteral, topical and suppository pharmaceutical forms.

Figure 2 .
Figure 2. DSC curves for medazepam, citric acid and their binary mixtures.

Figure 3 .
Figure 3. Peak deconvolution for binary mixtures with medazepam mole fractions of 0.9003 and 0.9519.

Figure 2 .
Figure 2. DSC curves for medazepam, citric acid and their binary mixtures.

Figure 2 .
Figure 2. DSC curves for medazepam, citric acid and their binary mixtures.

Figure 3 .
Figure 3. Peak deconvolution for binary mixtures with medazepam mole fractions of 0.9003 and 0.9519.

Figure 6 .
Figure 6.Variation in thermodynamic excess functions with medazep

Figure 6 .
Figure 6.Variation in thermodynamic excess functions with medazepam mole fraction.

Figure 6 .
Figure 6.Variation in thermodynamic excess functions with medazepam mole fraction.

Figure 7 .
Figure 7. IR spectrum of citric acid, medazepam and their eutectic mixture.

Figure 7 .
Figure 7. IR spectrum of citric acid, medazepam and their eutectic mixture.

Table 1 .
DSC data (x-mole fraction of medazepam, T-temperature, p = 99.1 kPa-pressure and ΔH-enthalpy) for citric acid, medazepam and their binary mixtures for mole fractions of medazepam x and temperatures T.

Table 1 .
DSC data (x-mole fraction of medazepam, T-temperature, p = 99.1 kPa-pressure and ∆H-enthalpy) for citric acid, medazepam and their binary mixtures for mole fractions of medazepam x and temperatures T.

Table 2 .
Thermodynamic excess functions (S E

Table 2 .
Thermodynamic excess functions (S E

Table 2 .
Thermodynamic excess functions (S E

Table 2 .
Thermodynamic excess functions (S E , G E and μ E ) and calcula citric acid-medazepam mixture.