Hydroquinoneexcipients.pdf

J Therm Anal Calorim (2015) 120:719–732 DOI 10.1007/s10973-014-4076-9

Compatibility study between hydroquinone and the excipients used in semi-solid pharmaceutical forms by thermal and nonthermal techniques I´gor Prado de Barros Lima • Naiana Gondim P. B. Lima • Denise M. C. Barros Thays S. Oliveira • Caˆndida M. S. Mendonc¸a • Euze´bio G. Barbosa • Fernanda N. Raffin • Tu´lio F. A. de Lima e Moura • Ana Paula B. Gomes • Ma´rcio Ferrari • Cı´cero F. S. Araga˜o

•

Received: 3 November 2013 / Accepted: 3 August 2014 / Published online: 29 August 2014 Ó Akade´miai Kiado´, Budapest, Hungary 2014

Abstract Thermal techniques, such as differential scanning calorimetry (DSC), thermogravimetry (TG), derivate of TG curve, differential thermal analysis, and non-thermal techniques such as fourier transform infrared (FTIR) spectroscopy and X-ray diffractometry (XRD) were used to evaluate the possible interactions between hydroquinone (HQ) and excipients commonly used in semi-solid pharmaceutical forms. The DSC curve of HQ showed a sharp endothermic event between 173 and 179 °C indicating melting point. No evidence of interaction was observed between HQ and cetyl alcohol (CA), cetostearyl alcohol (CTA), disodium ethylenediaminetetraacetate , and decyl oleate. However, based on the thermoanalytical trials, a physical interaction was suspected between HQ and dipropylene glycol (DPG), glycerin (GLY), hydroxypropyl methylcellulose (HPMC), imidazolidinyl urea (IMD), methylparaben (MTP), and propylparaben (PPP). The FTIR results show that for DPG, GLY, HPMC, MTP, and PPP, there were no chemical interactions with HQ at room temperature, but the heating promotes interaction between HQ and HPMC. The FTIR spectra of HQ/IMD show the chemical interaction at room temperature, which was also observed with heating. The XRD results of mixtures between HQ and DPG, HPMC, IMD, MTP, and PPP indicate no interaction between these substances at room

I´. P. de Barros Lima
N. G. P. B. Lima
D. M. C. Barros
T. S. Oliveira
C. M. S. Mendonc¸a
E. G. Barbosa
F. N. Raffin
T. F. A. de Lima e Moura
A. P. B. Gomes
M. Ferrari
C. F. S. Araga˜o (&) Department of Pharmacy, Federal University of Rio Grande do Norte, Rua Gen. 9 Cordeiro de Faria s/n, Rua Ju´lio Gomes Moreira 1113, 303 A, Bairro: Barro Vermelho, Natal, Rio Grande do Norte CEP 59.022-110, Brazil e-mail: [email protected]; [email protected]

temperature, but the heating modifies the HQ crystallinity in these mixtures. All of these methods showed incompatibility between HQ and the excipient IMD. Keywords Hydroquinone
Compatibility
Thermal analysis
FTIR
XRD

Introduction Hydroquinone is the most popular depigmenting agent, a phenolic compound chemically known as 1,4-dihydroxybenzene that inhibits the conversion of DOPA to melanin by tyrosinase inhibition. It covalently binds to histidine or interacts with copper at the active site of tyrosinase. It has been the gold standard for treatment of hyperpigmentation for many decades. It is also supposed to inhibit DNA and RNA synthesis and induce degradation of melanosomes and destruction of melanocytes [1, 2]. Hydroquinone is very difficult to formulate in a stable preparation. It is a highly reactive oxidant that rapidly combines with oxygen. Typically, HQ skin-lightening creams have a creamy color that changes to a darker yellow or brown as oxidation occurs. As the discoloration progresses, the HQ activity decreases. Products with any offcolor change should be immediately discarded [2]. This active pharmaceutical ingredient (API), what is HQ, is mixed with selected excipients to prepare semi-solid formulations for the treatment of hyperpigmentation. The successful formulation of a stable and effective semi-solid dosage form depends on the careful selection of the excipients used to make administration easier or more suitable, to improve patient compliance, to promote release and bioavailability of the drug, and protect it from degradation [3, 4].

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Excipients are known to facilitate administration and release of an active component, as well as protecting it from the environment. Furthermore, excipients are considered pharmaceutically inert, but physical and chemical interactions with active components are possible [4, 5]. The study of drug–excipients compatibility represents an important phase in the pre-formulation stage for the development of all dosage forms. In fact, potential physical and chemical interactions between drug and excipients can affect the chemical nature, stability and drug bioavailability and, consequently, their therapeutic efficacy and safety [3]. The thermoanalytical methods are useful at the preformulation stage to obtain information on the physicochemical properties and thermal behavior of the active substances, because they are related to its decomposition. Furthermore, data acquired at this stage are extremely important in critical decisions relating to subsequent phases of development [6]. Brazil Thermoanalytical techniques, especially differential scanning calorimetry (DSC), thermogravimetry (TG)/derivate of TG curve (DTG), and differential thermal analysis (DTA), have been used a long time ago by pharmacists for characterization of materials before their use and/or at any other stages of the pre-formulation [7–9]. The DTA analytical technique was used in this study, along with DSC, in order to recover the DTA technique for use in compatibility studies of pharmaceutical samples. The DTA, similar to the DSC, is used to measure the melting point and heat of fusion, and it has been used for more than five decades to evaluate interactions between substances [10, 11]. Several studies have confirmed that these techniques can be considered as important tools in the first stage of developing a formulation in the excipients selection [12–14]. There are several differences between these two techniques; DTA detects the temperature differences while the DSC detects changes in enthalpy (heat flow difference). The DTA is a robust technique and older than the DSC. On the other hand, the DSC is derived from DTA, being more sensitive than DTA. The DTA uses sample amount about four times greater than the DSC and has as the lV as unit (microvolts), since the DSC is expressed in mW (milliwatt). The open alumina crucible is used on the DTA, while for DSC is used closed aluminum crucible. By the combination of DTA and DSC techniques many overlapping stages can be observed and better interpreted [15]. Thermoanalytical trials have been proposed as a rapid method for the evaluation of physicochemical interactions between components of the formulation and, therefore, for selection of excipients. However, interpretation of the thermal data is not always simple, and it is necessary to avoid misinterpretation and unreliable conclusions thorough the evaluation [3]. Therefore, other analytic

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Table 1 Raw materials used in the compatibility study Sample

Classification

Provider

Active ingredient

Viafarma

Cetyl alcohol (CA)

Emulsifying agent; stiffening agent

Pharma special

Cetostearyl alcohol (CTA)

Emulsifying agent; stiffening agent

Henrifarma

Dipropylene glycol (DPG)

Humectant; cosolvent

Galena

Disodium EDTA (EDTA)

Chelating agent

Viafarma

API Hydroquinone (HQ) Excipients

Glycerin (GLY)

Humectant; emollient

Galena

Hydroxypropyl methylcellulose (HPMC)

Gelling agent; viscosityincreasing agent

Henrifarma

Imidazolidinyl urea (IMD)

Antimicrobial preservative

Fagron

Methylparaben (MTP)

Antimicrobial preservative

Pharma special

Decyl oleate (DCO)

Emolient

Galena

Propylparaben (PPP)

Antimicrobial preservative

Pharma special

techniques often have to be used to adequately interpret TA findings. Besides TA techniques, fourier transform infrared (FTIR) and X-ray diffractometry (XRD) have been used as a complementary method for the evaluation of possible interactions between the components [4]. Several reports are described in the literature to evaluate the interactions between drugs and excipients using thermal (DSC and DTA) and non-thermal (FTIR and XRD) techniques [4, 16–18]. The aim of the present work was to evaluate the possible interactions between HQ and excipients commonly used in semi-solid pharmaceutical forms using thermal (DSC, TG/ DTG and DTA) and non-thermal (FTIR and XRD) techniques.

Materials and methods Materials and samples Besides the API, the names, classification, and provider of the used excipients are listed in Table 1. The excipients selected are part of the composition of an anionic cream and a hydroxypropyl methylcellulose gel contained in the national formulary of Brazilian pharmacopeia [19]. Binary mixtures (BM) of HQ with each selected excipient were

Thermal and non-thermal techniques

prepared in the 1:1 (m/m) ratio by simple physical mixture of the components in agate mortar with pestle for 5 min. The 1:1 (m/m) ratio was chosen to maximize the probability of observing any interaction. Thermal techniques DSC curves were obtained in a Shimadzu DSC-60 cell, using closed aluminum pans with about 2 mg of samples, under dynamic atmosphere of N2 (flow rate of 50 mL min-1) and heating rate of 10 °C min-1 in the temperature range from 25 to 450 °C. Tests were carried out individually with API and excipients, then with recently prepared physical mixtures. Highly pure Zn and In were used to calibrate the DSC equipment, where experiments were run at 200 and 500 °C, respectively. Through their melting points (156.65 and 419.50 °C for In and Zn, respectively) the areas under the peaks were determined. Once the correction of the calibration temperature was performed, the heat calibration was corrected in which the enthalpy value for In and Zn was 28.5 and 100.5 J g-1, respectively. Further, new experiments were performed to assure that the melting temperature varied in the range of ±0.5 °C and the values of melting enthalpy (DH) in the range of ±1.0 J g-1. Once these parameters were reached, the calibration was accomplished. TG and DTA curves were obtained on a SHIMADZU thermobalance model TGA 60 (simultaneous TG/DTA), using alumina pan (about 8 mg samples), heating rate of 10 °C min-1 in the 25–900 °C temperature range, under dynamic atmosphere of N2 at 50 mL min-1. Tests were carried out individually with API and excipients, then with recently prepared physical mixtures. The TGA 60 equipment was calibrated using In which was heated up to 200 °C followed by correction of the calibration temperature. Next, another experiment was run with the purpose of checking whether the melting temperature varied in ±0.5 °C. Thermal curves were analyzed with the aid of the SHIMADZU software TASYS to identify thermal events presented as well as the temperatures (Tonset, and Tpeak) and energies (J g-1) involved in these events. Non-thermal techniques Fourier transform infrared spectroscopy in transmittance mode was used. KBr pellets with 1 % mass of the powdered material were produced. The spectra were obtained using a PerkinElmer FTIR spectrometer, model SpectrumTM 65, in the spectral area 400–4,000 cm-1, with a resolution 0.5 cm-1.

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In order to detect interactions between the active and excipients ingredients, a correlational IR analysis was performed. Such analysis was carried out by importing the IR spectral data in Spectrum 10 software. The spectral region from 400 to 4,000 cm-1 was considered in this approach. A theoretical IR spectrum of the active and excipients ingredients was built to establish a comparison with the linear combination of the BM’s experimental spectra. Subsequently, the Pearson’s correlation (r) between the theoretical and experimental drug–excipient IR spectra was calculated. The deviation from ideality (r = 1) was interpreted as indication of problems for a particular drug–excipient mixture analyzed. The comparison of the IR spectra of pure drug and BM drug/excipient is widely used in the pharmaceutical literature. The XRD of the samples was obtained in a Shimadzu X-ray diffractometer model Maxima_X XRD-7000, with X-ray tube sealed type using a Cu ka radiation. The scanned range was 5–80° (2h). The equipment was operated on 40.0 kV, 30.0 mA. Data were plotted by means of the software Origin version 8.0. Analyses were performed in the FTIR spectra and XRD with pharmaceutical raw materials at room temperature and heat treated at 190 °C. For heating, samples were placed on a Kline plate with 12 excavation and then heated on a Quimis drying oven model Q317 M in the heating rate of 5 °C min-1 to the temperature of 190 °C.

Results and discussion Thermal behavior of HQ In Fig. 1a, the DSC curve of HQ is presented revealing important information. An analysis of the DSC curve of HQ confirmed the presence of two endothermic events characteristic of the thermal behavior of this material. The DSC curve of HQ showed a sharp endothermic event (event 1) between 173 and 179 °C indicating the melting (Tonset 173 °C, Tpeak 176 °C, DH 258 J g-1). This peak corresponds to the HQ melting, and it is consistent with the melting range values described in the literature (between 172 and 174 °C) [20]. The second event observed (event 2) in the DSC curve was also an endothermic one between 180 and 246 °C (Tonset 180 °C, Tpeak 244 °C). The TG/DTG curve (Fig. 1a) showed that HQ was thermally stable up to 135 °C and then one mass loss stage could be observed. The mass loss (98.2 % decrease) occurred in the temperature range from 135 to 226 °C, with Tonset TG 149 °C. The DTG presented one peak (Tonset DTG 172 °C, Tpeak DTG 217 °C) corresponding to the mass loss observed in the TG.

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722

100

30

60

DTA

1

10 40

0

0

–100

–10

4

20

3

50

100

2 Mass loss/%

100

80

2

20 DTG

Endo

200

Heat flow/mW

DSC

–0

150

200

250

4

0

–2

7000

Intensity/a.u. Intensity/a.u.

b

TG

300

First derivate/mg min–1

a Temperature difference/μV

Fig. 1 a DSC, TG/DTG, and DTA curves of HQ; b X-ray diffractogram of HQ at room temperature and heated at 190 °C; c FTIR spectra of HQ at room temperature and heated at 190 °C

HQ at room temperature

0 7000

20

30

40

10

20

30

40

300

a

Transmitance/% Transmitance/%

CTA DPG

80

HQ heated at 190 °C

20 0 4000

3500

3000 2500 2000 1500 Wavenumber/cm–1

1000

500

HQ HPMC

0

IMD MTP

Endo

GLY

Endo

70

40

–20

EDTA

DCO PPP

–40 50

100

150

200

250

300

50

100

Temperature/°C

c

150

200

250

300

250

300

Temperature/°C

d

HQ

HQ 10

10

HQ/CA

0

HQ/HPMC

Heat flow/mW

Heat flow/mW

60

20

Heat flow/mW

Heat flow/mW

CA

HQ/CTA HQ/DPG

–10

HQ/EDTA

–20

0

HQ/IMD

–10 HQ/MTP HQ/DCO –20 HQ/PPP

HQ/GLY –30

–30 50

100

150

200

250

300

Temperature/°C

Endo

Endo

50

40

20

0

–40

80

HQ at room temperature

HQ

–20

70

OH

HO

60

b

20

60

2θ /°

Temperature/°C

c

50

HQ heated at 190 °C

0

–4

10

50

100

150

200

Temperature/°C

Fig. 2 DSC curves of all substances used in compatibility study: a and b HQ and excipients, c and d HQ and its 1:1 (m/m) mixtures

The DTA curve (Fig. 1a) showed the first endothermic event (event 3) between 173 and 184 °C indicating the melting (Tonset 173 °C, Tpeak 176 °C, DH 1,270 J g-1) and

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the second one (event 4—also endothermic) between 185 185 °C, Tpeak 219 °C, and 244 °C (Tonset -1 DH 1,940 J g ).

Thermal and non-thermal techniques

b

HQ

HQ

CTA

–100

DPG

–200

EDTA GLY

–300 –400 –500 50

100

150

200

250

0 HPMC IMD

–100 MTP DCO

–200

PPP

–300 Endo

CA

Temperature differance/μV

0

Endo

Temperature differance/μV

a

723

–400

300

50

100

Temperature/°C

HQ/CTA

–100

HQ/DPG

–200

HQ/EDTA HQ/GLY

–300

–400 50

250

300

100

150

200

250

250

300

HQ

0

HQ/HPMC

–100

HQ/IMD HQ/MTP

–200 HQ/DCO

–300 HQ/PPP Endo

HQ/CA

Temperature differance/μV

0

200

d

HQ

Endo

Temperature differance/μV

c

150

Temperature/°C

–400

300

50

100

Temperature/°C

150

200

Temperature/°C

Fig. 3 DTA curves of all substances used in compatibility study: a and b HQ and excipients, c and d HQ and its 1:1 (m/m) mixtures

Table 2 Temperatures and DH values of melting peak for physical mixtures in DSC curve

Table 3 Temperatures and DH values of melting peak for physical mixtures in DTA curve

Excipient in 1:1 mixture

Tonset/°C

Tpico/°C

DH/J g-1

Excipient in 1:1 mixture

Tonset/°C

Tpico/°C

DH/J g-1

HQ/CA

172

175

157

HQ/CA

168

172

HQ/CTA

173

175

58

HQ/CTA

167

173

353

HQ/DPG HQ/EDTA

165 175

167 177

14 166

HQ/DPG* HQ/EDTA

170 171

214 175

3,110 564

HQ/GLY

174

184

60

HQ/GLY*

191

228

4,120

HQ/HPMC*

–

–

–

HQ/HPMC*

175

213

1,440

HQ/IMD*

–

–

–

HQ/IMD

152

164

845

HQ/MTP*

–

–

–

HQ/MTP*

194

224

2,640

HQ/DCO

175

177

67

HQ/DCO

171

175

524

HQ/PPP*

–

–

–

HQ/PPP

141

158

207

HQ

173

176

258

HQ

173

176

1,270

316

* Physical mixtures in which the melting peak of HQ was not observed

* Presence of a single event with the junction of two characteristics events

Compatibility study with excipients

The DSC curve of HQ/CA BM (Fig. 2c) shows a first characteristic peak of the CA excipient (occurring between 50 and 55 °C) and two other events characteristic of HQ. The melting peak of HQ is observed in this BM at temperatures (Tonset, and Tpeak—as can be seen in Table 2) very similar to those temperatures of HQ alone, and the DH involved in this event has its value reduced from 258 to 157 J g-1 (Table 2). Analyzing the DTA curve of HQ/CA BM (Fig. 3c), a similar behavior to that found in the DSC

The selection of adequate excipients for formulation should be based on the drug characteristic and its compatibility and stability with other components [21]. Figures 2a, b and 3a, b show DSC and DTA curves of all substances isolated (HQ and excipients) used in the compatibility study. The DSC and DTA curves of HQ-excipients mixtures are shown in Figs. 2c, d and 3c, d.

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curve of the same BM is observed, where a first characteristic peak of the excipient and two other events of HQ. In the DTA curve, the melting peak of HQ is also observed in this BM at very similar temperatures to those of HQ alone, but the DH involved in this event has its value greatly reduced (Table 3). In the DSC curve of HQ/CTA BM (Fig. 2c), the melting peak of HQ occurred in this BM at temperatures (Tonset, and Tpeak—Table 2) very similar to those temperatures of HQ alone, but the DH involved in this event has its value strongly reduced from 258 to 58 J g-1 (Table 2). In the DTA curve of HQ/CTA BM (Fig. 3c), the melting peak of HQ occurred also in this BM at very similar temperatures to those of HQ alone, but the DH involved in this event has its value strongly reduced from 1,270 to 353 J g-1 (Table 3). The similarity in the thermal behavior of CA and CTA in this compatibility study can be explained by the similarity in the chemical structures of these pharmaceutical excipients, which also have the same function (emollient; emulsifying) in semi-solid pharmaceutical forms. Evaluating the DSC and DTA curves of HQ/EDTA BM (Figs. 2c, 3c), the melting peak of HQ happened in this BM at temperatures (Tonset, and Tpeak—Tables 2, 3) very similar to those of HQ alone. In the 1:1 physical mixtures, where there is no any interaction between substances, the stages of heat flow should remain virtually unchanged, similarly to when the drug is alone. Through the comparison of the DSC and DTA curves of HQ, CA, CTA, EDTA, and the BM of these compounds, it was concluded for a little change in the thermal stability of HQ in those mixtures (slight changes in Tonset, and Tpeak), suggesting no interaction between these substances, even with some reductions in the DH involved in the characteristic events of HQ. In the DSC curve, the DH for the HQ corresponds to 258 J g-1, the value expected in a 1:1 mixture is close to 129 J g-1 and in the DTA curve, the DH corresponds to 1,270 J g-1, the value expected in a 1:1 mixture is close to 635 J g-1; however, reductions isolated in the DH without significant changes in temperatures (Tonset, and Tpeak) not necessarily represent drug–excipient interaction. The small variations in the enthalpy’s values for BM can be attributed to some heterogeneity in the small samples used for the DSC experiments (3–4 mg). Data from the DSC and DTA curves of these substances were very similar, showing substantial complementarity of these thermoanalytical techniques. However, when evaluating the DSC curve of HQ/DPG BM (Fig. 2c), the melting peak of HQ on this BM has its temperatures (Tonset and Tpeak—Table 2) anticipated to lower values. The DH of the melting of HQ in the BM has its value reduced to an appreciable extent from 258 to

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14 J g-1 (Table 2). When evaluating the DTA curve of HQ/DPG BM (Fig. 3c), there is a junction (overlapping) of two events characteristic of the drug, showing a single event. This event presents Tonset virtually unchanged, but the Tpeak is shifted to higher temperature, undergoing the Tpeak from 176 to 214 °C (Table 3). With respect to the DH involved, there is increase in their values from 1,270 to 3,110 J g-1 (Table 3), which can be explained only by the junction of events in this BM. With the objective of better explain the processes occurring in this HQ/DPG BM, Fig. 4a shows the TG/DTG curves of this BM. The TG curve of HQ/DPG (Fig. 4a) shows one mass loss stage has its Tonset anticipated to lower values (from 182 to 167 °C), and in the DTG curve of this BM (Fig. 4a), there is anticipation of Tonset and Tpeak to lower values. Thus, the anticipation to lower values of melting peak of HQ in the DSC curve of the HQ/DPG BM, allied to the combination of events in the DTA curve, and together with anticipation of Tonset and Tpeak to lower values in the TG/ DTG curves, is indicative of interaction of HQ with DPG. These data obtained from the thermal curves of HQ/ DPG mixture indicate a possible interaction with this excipient, which can be attributed to the almost complete drug dissolution in liquid pharmaceutical excipient. The same behavior was observed in the compatibility study of Salvio Neto et al. [17], where due to the complete drug dissolution in the melt of the excipient, no melting of prednicarbate was observed in the DSC curve of the prednicarbate/stearyl alcohol mixture. In regards to the DSC curve of HQ/GLY BM (Fig. 2c), the melting peak of HQ on this BM has its temperatures (Table 2) shifted to higher values, mainly Tpeak, but the DH involved in this event has its value strongly reduced from 258 to 60 J g-1 (Table 2). When observing the DTA curve of HQ/GLY BM (Fig. 3c), it is possible to see a junction (overlap) of two characteristic events of the HQ, showing a single event. This event presents the temperatures shifted to higher temperatures, undergoing the Tonset from 173 to 191 °C and Tpeak from 176 to 228 °C. With respect to the energies involved, there is increased values from 1,270 to 4,120 J g-1 (Table 3), which can be explained only by the junction of events in this BM. In the same way as for the HQ/DPG, with the objective of explain the processes occurring in HQ/GLY BM, Fig. 4b shows the TG/DTG curves of this BM. The TG curve of HQ/GLY (Fig. 4b) shows one mass loss stage has its Tonset slightly shifted to higher temperature, from 182 to 184 °C, and in the DTG curve (Fig. 4b), there is also displacement to higher temperature, Tonset DTG from 172 to 182 °C and Tpeak DTG from 217 to 226 °C. Thus, DSC and TG/DTG curves of HQ/GLY BM do not show shifts in these curves of HQ for lower temperatures,

Thermal and non-thermal techniques

–5

HQ/DPG

0 200

300

400

500

600

700

800

–5

HQ/GLY

900

100

200

300

Temperature/°C

500

600

700

800

0

HQ/IMD

IMD HQ

50

100

–2

MTP

–4 200

300

400

500

600

Temperature/°C

200

300

700

800

900

400

500

600

700

800

900

f 0

HQ

–3

0 100

–8

0

Temperature/°C

HQ HQ/MTP MTP

–1

IMD HQ/IMD

100

First derivate/mg min–1 Mass loss/%

HQ

–6

HQ/HPMC

900

e

100

HPMC

Temperature/°C

d Mass loss/%

400

–4

50

–10

0

–10 100

50

–2

HQ

First derivate/mg min–1

50

HQ GLY

0

HPMC

HQ/HPMC

50

–5

HQ/MTP

0

–10 100

200

300

400

500

600

Temperature/°C

700

800

900

0

HQ

100

HQ/PPP PPP HQ PPP

50

–5

HQ/PPP

First derivate/mg min–1

DPG

HQ

100 0

First derivate/mg min–1 Mass loss/%

HQ

c HQ HQ/GLY GLY

Mass loss/%

HQ/DPG

100

First derivate/mg min–1

Mass loss/%

DPG

b

0

Mass loss/%

HQ

100

First derivate/mg min–1

a

725

–10

0 100

200

300

400

500

600

700

800

900

Temperature/°C

Fig. 4 TG/DTG curves of possible interactions of HQ with the excipients: a HQ, DPG, and HQ/DPG; b HQ, GLY, and HQ/GLY; c HQ, HPMC, and HQ/HPMC; d HQ, IMD, and HQ/IMD; e HQ, MTP, and HQ/MTP; f HQ, PPP, and HQ/PPP

indicating no interaction between these substances through these techniques, but the junction of events in the DTA curve of the HQ/GLY BM indicates that the other analytical method must be used for this mixture aiming at investigating whether there is interaction between HQ and GLY. In the DSC curve of HQ/HPMC BM (Fig. 2d), no characteristic events of HQ were observed, including the melting peak of HQ which was absent. When analyzing the DTA curve of HQ/HPMC BM (Fig. 3d), it is possible to observe a junction (overlap) of two events characteristic of the HQ, showing a single event. This event presents the temperatures shifted to higher temperatures, undergoing the Tonset from 173 to 175 °C and Tpeak from 176 to 213 °C, and the DH involved in this event has its value increased from 1,270 to 1440 J g-1 (Table 3). The TG curve of HQ/HPMC (Fig. 4c) shows two mass loss stages, being the first stage corresponding to the decomposition of HQ, and has its Tonset slightly anticipated to lower values, and in the DTG curve of this BM (Fig. 4c), there is two peaks, the first corresponding to the drug decomposition, and in this peak, slight anticipation of Tonset and Tpeak to lower values, Tonset DTG from 172 to 162 °C, and Tpeak DTG from 217 to 214 °C happens. The absence of characteristic events of HQ in the DSC curve of the HQ/HPMC BM, allied to the junction of events in the DTA curve, is indicative of interaction of HQ with HPMC. In the DSC curve of HQ/IMD BM (Fig. 2d), no characteristic events of HQ were observed, including the melting peak of HQ, which was absent. For the DTA curve of HQ/IMD BM (Fig. 3d), the melting peak of HQ is

markedly anticipated to lower temperatures, mainly Tonset which was reduced from 173 to 152 °C (Table 3), corresponding to a reduction of more than 10 % of Tonset of HQ alone. The DH involved in this event has its lower value change from 1,270 to 845 J g-1 (Table 3). The TG curve of HQ/IMD (Fig. 4d) shows three mass loss stages, being the first stage corresponding to the decomposition of HQ, and has its Tonset slightly anticipated to lower values, and in the DTG curve of this BM (Fig. 4d), there is two peaks, the first corresponding to the drug decomposition and the second to the IMD. In the HQ/IMD, decomposition peak happens strong anticipation of Tpeak to lower value, Tpeak DTG from 217 to 165 °C. Thus, the absence of characteristic events of HQ in the DSC curve of the HQ/IMD BM, combined with extensive anticipation of the melting peak of HQ in DTA curve, allied to the anticipation of Tonset to lower values in the TG curve, and disappearance of the HQ peak in the DTG curve are indicative of strong interaction of HQ with IMD. The evaluation of the DSC and DTA curves of HQ/DCO BM (Figs. 2d, 3d), shows the melting peak of HQ happened in this BM at very similar temperatures to those of HQ alone, but the DH involved in this event has its value reduced (Tables 2, 3). Through the comparison of the DSC and DTA curves of these compounds, it was concluded that the thermal stability of HQ in this mixture changed a little, suggesting no interaction between these substances. The DSC curve of HQ/MTP BM (Fig. 2d) assumes practically the same behavior of the DSC curve of MTP, and no characteristic events of HQ were observed, including the melting peak of HQ, which was absent. However, there is the presence of an event between 110

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and 120 °C, which corresponds to a characteristic peak of MTP. By analyzing the DTA curve of HQ/MTP BM (Fig. 3d), it is possible to observe an event happening between 109 and 123 °C, which corresponds to a characteristic peak of MTP. After this, it is possible to observe a junction (overlap) of two events characteristic of the HQ, showing a single event. This event presents the temperatures shifted to higher temperatures, undergoing the Tonset from 173 to 194 °C and Tpeak from 176 to 224 °C, and the DH involved in this event has its value increased from 1,270 to 2,640 J g-1 (Table 3). The TG curve of HQ/MTP (Fig. 4e) shows one mass loss stage, it has its Tonset slightly shifted to higher temperature from 182 to 183 °C, and in the DTG curve (Fig. 4e,) there is also displacement to higher temperature, Tonset DTG from 172 to 175 °C and Tpeak DTG from 217 to 223 °C. From these considerations, the absence of characteristic events of HQ in the DSC curve of the HQ/MTP BM, combined with the junction of events in the DTA curve, is indicative of interaction of HQ with MTP. In the study of Lira et al. [22], the same behavior was observed with MTP; there was an appreciable downward shift of the drug peak temperature in the thermal curve of the BM of lapachol/MTP, which can be indicative of some drug–excipient solid interaction. DSC curves showed that the peak at around 139 and 124 °C, which was observed for lapachol and MTP, respectively, disappeared in the eutectic mixture. The DSC curve of HQ/PPP BM (Fig. 2d) assumes practically the same thermal behavior of the DSC curve of MTP, and no characteristic events of HQ were observed, including the melting peak of HQ. By comparing the DTA curves (Fig. 3d) of pure HQ and PPP with their 1:1 physical mixture, a first peak that is characteristic of PPP (between 89 and 103 °C) and two other characteristic events of HQ are observed. For the DTA curve of HQ/PPP BM (Fig. 3d), the melting peak of HQ is markedly anticipated to lower temperatures, Tonset which was reduced from 173 to 141 °C and Tpeak reduced from 176 to 158 °C (Table 3), corresponding to a reduction of more than 15 % of Tonset of HQ alone. The DH involved in this event has its value considerably reduced from 1,270 to 207 J g-1 (Table 3). The TG curve of HQ/PPP (Fig. 4f) shows one mass loss stage, and has its Tonset slightly shifted to higher temperature, from 182 to 183 °C, and in the DTG curve (Fig. 4f), there is also displacement to higher temperature, Tonset DTG from 172 to 175 °C and Tpeak DTG from 217 to 224 °C. From these considerations, the absence of characteristic events of HQ in the DSC curve of the HQ/PPP BM, combined with extensive anticipation of the melting peak

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of HQ in DTA curve, is indicative of interaction of HQ with PPP. In another study of compatibility [22], there was no interaction between the PPP and the API (lapachol), whose the physical mixture of lapachol and PPP in the DSC curve can be considered to be the superposition of the DSC curves of the two individual components. These results show that physical interactions of components did not occur within the mixture. Photovisual DSC was used to confirm the results obtained by conventional DSC. These data are not supported by the results found in our compatibility study with HQ/PPP BM. Another analytical technique used in this study was the FTIR spectroscopy that is a simple technique for the detection of changes within drug–excipient mixtures. The FTIR spectra of HQ at room temperature (Fig. 1c) showed the characteristic absorption bands of 1,4-disubstituted mononuclear aromatic ring and symmetrical secondary phenol group. The broad and medium intensity band at 3,269 cm-1 is due to the hydrogen bonded OH stretching vibration. The aromatic overtones and combination bands appearing from 2,010 to 1,740 cm-1 region confirm the presence of aromatic system. The intense band at 2,856 cm-1 represents C–H stretching vibration. The bands at 1,635 and 1,516 cm-1 are consistent with the skeletal vibrations of the aromatic system. The bands at 1,388 and 1,353 cm-1 are due to the O–H in-plane bending vibrations. The absorptions at 1,095 cm-1 are due to C–O stretching vibrations. The substitution pattern is established by strong C–H out-of-plane bending absorptions at 827 and 759 cm-1. These data of FTIR spectrum are consistent with those reported in the literature [23], confirming that the substance is HQ and not indicating the presence of any other species. The FTIR spectra at room temperature of HQ, excipients and its 1:1 (m/m) physical mixtures with DPG, GLY, HPMC, IMD, MTP, and PPP are shown in Fig. 5. In this study, the analyses were performed in the FTIR spectra with the excipients mentioned above because in the thermoanalytical trials, we observed possible interactions in the BM of HQ with these excipients, thus the FTIR spectra acts as a complementary method for the evaluation of possible interactions between components. The evaluation of the FTIR spectra of 1:1 (m/m) physical mixtures between HQ/DPG, HQ/GLY, HQ/HPMC, HQ/MTP, and HQ/PPP (Fig. 5a, b, c, e, and f, respectively), clearly shows that the spectra of these BM are the result of the sum of the characteristic bands of individual components. However, note for the five mixtures (HQ/ DPG, HQ/GLY, HQ/HPMC, HQ/MTP, and HQ/PPP) in the spectra cited above that the absorption bands of the excipients may be overlapping the skeletal vibrations of the aromatic system of HQ at 1.635 cm-1 without any

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Fig. 5 FTIR spectra of HQ, excipients and its 1:1 (m/m) mixtures at room temperature: a HQ, DPG, and HQ/DPG; b HQ, GLY, and HQ/GLY; c HQ, HPMC, and HQ/HPMC; d HQ, IMD, and HQ/IMD; e HQ, MTP, and HQ/MTP; f HQ, PPP, and HQ/PPP

suggestion of interaction. Therefore, no chemical interactions occur between these substances at room temperature. In another study of compatibility [16], there was interaction between the propylene glycol excipient and the active ingredient (lipoic acid), whose active and excipient bands in the DSC scan of lipoic acid/propylene glycol mixture were missing. DSC results points toward some incompatibility between lipoic acid/propylene glycol mixture. Furthermore, IR spectra of the lipoic acid/propylene glycol blend did not show characteristic bands of lipoic acid at 3,030 and 945 cm-1, but presented a reduction of intensity of the band at 1,250 cm-1. Thus, the results obtained in the compatibility study of HQ with DPG are not in agreement with the data found in the aforementioned compatibility study. According to the results of the thermal studies, some changes in the FTIR spectra of mixtures of HQ, and some of the excipient suggested a possible interaction between the mixtures components, in agreement with the thermal analysis findings. For instance, FTIR spectra of HQ/IMD at room temperature (Fig. 5d) does not show the bands at 3,269 cm-1 (relating to the hydrogen bonded OH stretching vibration), at 1,740 cm-1 (relating to the aromatic system), and at 1,635 cm-1 (consistent with the skeletal vibrations of the aromatic system). Besides the disappearance of these bands mentioned above, there is the appearance of new bands at 1,725 and 1,672 cm-1. Then, there is a marked change in the FTIR spectra of HQ in the mixture with the IMDto get a clear evidence for chemical interaction between the HQ and IMD at room temperature.

These results of FTIR are in agreement with reports in the literature indicating that the disappearance of an absorption peak or reduction of the peak intensity combined with the appearance of new peaks give a clear evidence for interactions between the excipient and the drug investigated [24]. In the compatibility study of Moyano et al. [16], there was no interaction between the pharmaceutical preservative (IMD) and the API(lipoic acid), where the melting of lipoic acid was well retained in the DSC scan of lipoic acid/IMD mixture, the band corresponding to lipoic acid was observed without any new bands. Furthermore, IR spectra of lipoic acid and its blend with the above mentioned excipient IMD showed the presence of characteristic bands corresponding to lipoic acid. Thus, the results obtained in the compatibility study of HQ with IMD are not in agreement with the data found in the compatibility study cited above. Studies are constantly being conducted on the elaboration of efficient methods to confirm the compatibility of API and excipients, and scholars have continued to find new more effective methods in the identification of incompatibilities. Therefore, the analysis of the FTIR spectra of drug/excipient BM was also conducted by a quantitative method of Pearson’s correlation (r), the statistical methodology, generated by a computer that mathematically calculated the difference between the theoretical and experimental FTIR spectra. We propose that the more the computed correlations deviate from the unit (1.00), the more drug–excipient interactions are present.

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Wesolowski et al. [25], conducted an evaluation of the utility of the two chemometric methodologies, hierarchical cluster analysis (HCA) and principal component analysis (PCA), as supporting techniques for the identification of potential incompatibilities that can occur in the pre-formulation stage of a solid dosage drug form. The investigation performed with the use of baclofen and selected excipients has shown that with thermogravimetric analysis, HCA, and PCA fulfill their role as supporting techniques in the interpretation of the data obtained. The Fig. 6 shows the results of such analysis. It can be observed that the HQ/IMD mixture (r1 = 0.7301) was the sample that mostly deviated from the ideal correlation, indicating moderate correlation between the FTIR spectra. The literature [26, 27] reported that the Pearson’s correlation (r) close to unity (1.00) shows that the variables being compared are similar. When the value of r is between 0.80 and 1.00, indicating high correlation, while between 0.5 and 0.80 shows moderate correlation, and r less than 0.50 indicates a low correlation between variables compared. This can be related to a chemical reaction of HQ and IMD molecules resulting in a greater difference in the FTIR spectra, showing that there is evidence that the IMD released formaldehyde and thus oxidized the HQ. The second most unstable mixture is the HQ/GLY (r2 = 0.8399), followed by HQ/DPG (r3 = 0.9050), and HQ/PPP (r4 = 0.9329). The FTIR spectra of HQ/HPMC (r5 = 0.9877) and HQ/MTP (r6 = 0.9899) showed almost perfect correlation with the theoretical FTIR spectra of HQ. The Pearson’s correlation showed a small deviation of FTIR spectrum of HQ, indicating a high correlation between the theoretical and experimental FTIR spectra,

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confirming no chemical interaction between the HQ and the excipients mentioned above. Thus, the Pearson’s correlation provided a more precise mathematical analysis of the FTIR spectra of the samples analyzed in this compatibility study. The advantage of the FTIR spectra correlation analysis in comparison to the TA is the lack of heat-induced alterations in the mixture. The HQ was heated at 190 °C to be analyzed by FTIR aiming at evaluating the chemical stability of the drug depending on the heating, and this temperature (after the melting point of HQ) was selected based on thermal characterization performed by DSC and DTA curves of the drug alone. The FTIR spectra of HQ heated at 190 °C showed (Fig. 1c) virtually the same profile FTIR spectra of HQ at room temperature, except for the absorption bands at 1,635 and 1,618 cm-1 that became overlapping with the heating, thus showing only one band in 1,637 cm-1. In the study of Fulias et al. [28], a heating of pharmaceutical substances (phenazone, and phenylbutazone) was conducted followed by FTIR analysis aiming at characterizing such samples at room temperature and treated with heating. In compatibility study of HQ were conducted also heating at 190 °C of excipients and BM of HQ with excipients to perform FTIR analysis, with the aim of evaluating the influence of heating on chemical interactions between the drug and excipient. The BM selected for the heating at 190 °C were those that showed incompatibilities in thermal and FITR analysis at room temperature. The FTIR spectra of HQ, excipients and its 1:1 (m/m) physical mixtures with excipients heated at 190 °C are shown in Fig. 7. In the study of Lima et al. [29], heating of BM of the trioxsalen drug with various pharmaceutical excipients was performed, and then the FTIR analyses were performed with the aim of investigating the influence of heating in the appearance of chemical interactions in the drug–excipient mixtures. The evaluation of the FTIR spectra of physical mixtures heated at 190 °C between HQ/DPG, HQ/GLY, HQ/MTP, and HQ/PPP (Fig. 7a, b, e, and f, respectively), clearly shows that the spectra of these BM are the result of the sum of the characteristic bands of individual components, being in the same manner as observed for the same mixtures at room temperature. However, noted for the two mixtures (HQ/MTP and HQ/PPP) the disappearance of the absorption band (at 1,637 cm-1) of the skeletal vibrations of the aromatic system of HQ heated at 190 °C, without any suggestion of interaction. Thus, indicating that no chemical interactions occur between these substances heated at 190 °C. The FTIR spectra of HQ/HPMC BM heated at 190 °C (Fig. 7c) show a change in behavior with the heating,

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Fig. 7 FTIR spectra of HQ, excipients and its 1:1 (m/m) mixtures heated at 190 °C: a HQ, DPG, HQ/DPG; b HQ, GLY, HQ/GLY; c HQ, HPMC, HQ/HPMC; d HQ, IMD, HQ/IMD; e HQ, MTP, HQ/MTP; f HQ, PPP, HQ/PPP

because there is mainly the disappearance of the absorption bands at 1,858 cm-1 (which indicates the presence of the aromatic system), 1,354 cm-1 (O–H in-plane bending vibrations) and 1,096 cm-1 (C–O stretching vibrations). Thus, it can be said that the heating to 190 °C provides the appearance of a chemical interaction between HQ and HPMC, which was not observed at room temperature. The FTIR spectra of HQ/IMD heated at 190 °C (Fig. 7d) besides not show bands at 3,269, 1,740, and 1,637 cm-1 as also was observed at room temperature, the heating promoted the disappearance of the bands at 2,856 and 2,010 cm-1 confirming the chemical interaction with the heating, which was also observed at room temperature. Another analytical technique used in this study was the XRD, a direct measure of the crystal form of a material being a plot of intensity versus the diffraction angle (2h). A crystalline material exhibits a unique set of diffraction peaks and the lack of crystalline API peaks, when a dosage form is analyzed could indicate that the material is amorphous or that the loading is too low to detect using the parameters chosen. XRD analysis is of immense help in case of incompatibilities which can occur during processes for selection of suitable excipients [30]. The XRD patterns of HQ at room temperature and HQ heated at 190 °C have been represented in Fig. 1b. The XRD for HQ at room temperature, exhibited sharp characteristic peaks, revealing its high crystallinity, which can be used as a fingerprint. The diffraction peak corresponding to the highest intensity was observed at 2h° value at 20.25°. Also, other important diffraction peaks were observed at 9.42°, 16.07°, 16.27°, 16.84°, 21.36°, and 30.60°.

As said before, the HQ was heated at 190 °C to be analyzed by XRD aiming to evaluate the crystallinity of the drug as a function of heating. Thus, the Fig. 1b shows that in the HQ heated at 190 °C occurs a slight change at 2h° value (in the pattern of crystallinity) compared to the HQ at room temperature, because with the heating, the main diffraction peaks can be observed in the sample heated, but with a reduction in the intensity of some peaks (mainly at 9.42°), however, do not show loss of crystallinity in the HQ heated. The XRD pattern of HQ, excipients and its 1:1 (m/m) physical mixtures with excipients at room temperature are shown in Fig. 8. The BM selected for the XRD were those that shown incompatibilities in the thermoanalytical trials and FITR analysis. The evaluation of the XRD of mixtures between HQ/ DPG at room temperature (Fig. 8a) clearly shows that the important diffraction peaks (as in 2h° values of 9.42°, 16.07°, 16.27°, 16.84°, 20.25°, and 21.36°), which are characteristic of crystallinity of HQ, remain practically unchanged in this BM, except for the peak at 30.6° which practically disappears in the mixture. However, when the XRD of HQ/DPG heated at 190 °C is analyzed (Fig. 9a), the disappearance of almost all important diffraction peaks of HQ is observed, and there is the formation of a new peak at 21.36° (high intensity). Thus, the XRD of HQ/DPG indicates no interaction between these substances at room temperature, but the heating modifies the HQ crystallinity. The XRD of HQ/GLY at room temperature (Fig. 8b) clearly shows that the important diffraction peaks, which are characteristic of HQ crystallinity, remain practically

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unchanged in this BM, except for the peak at 28.91° that increases its intensity in the mixture. The XRD of HQ/GLY heated at 190 °C (Fig. 9b) can be considered as the overlap of individual components without absence, shift or broadening substantial of the peaks of HQ heated. Therefore, the XRD of HQ/GLY indicates no interaction between these substances at room temperature, and heated.

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The XRD of HQ/HPMC and HQ/IMD at room temperature (Fig. 8c, d, respectively), clearly show that the important diffraction peaks, remain practically unchanged in these BM, showing the overlap of individual components without absence, shift or broadening substantial of the peaks of HQ. In the XRD of HQ/HPMC and HQ/IMD heated at 190 °C (Fig. 9c, d, respectively), the

Thermal and non-thermal techniques

disappearance of all important diffraction peaks of HQ heated is observed. Thus, the XRD of HQ/HPMC and HQ/ IMD indicates no interaction between these substances at room temperature, but the heating modifies the crystallinity of the HQ, indicating interaction with heating between HQ/ HPMC and HQ/IMD. The XRD of HQ/MTP and HQ/PPP at room temperature (Fig. 8e, f, respectively) clearly show that the important diffraction peaks, remain practically unchanged in these BM, showing the overlap of individual components without absence, shift or broadening substantial of the peaks of HQ. However, in the XRD of HQ/MTP and HQ/PPP heated at 190 °C (Fig. 9e, f, respectively), the disappearance of important diffraction peaks of HQ at 16.07°, 16.27°, and 30.6° is observed. In the XRD of HQ/MTP heated (Fig. 9e), there is the formation of a new peak at 23.07° (high intensity). Therefore, the XRD of HQ/MTP and HQ/PPP indicate no interaction between these substances at room temperature, but the heating modifies the HQ crystallinity, indicating interaction with heating between HQ/MTP and HQ/PPP. In the present study, the interactions suggested were mainly observed in the results obtained by thermal techniques (DSC, DTA, and TG/DTG), but in the mixture of HQ with IMD, both by thermal as the non-thermal (FTIR, and XRD) techniques, there was interaction between these components, showing a strong correlation between results obtained by these analytical techniques. The literature shows that IMD is one of the most widely used preservative system in the world; it is a broad-spectrum antimicrobial preservative used in cosmetics and topical pharmaceutical formulations; typical concentrations used are 0.03–0.5 % m/m. It is effective between pH 3–9 and is reported to have synergistic effects when used with parabens (MTP and PPP) [31]. It is known that pharmaceutical excipients commonly used in oral solid dosage forms might also be sources of formaldehyde. The results found in the study of Fujita et al. [32] showed that the formaldehyde is generated by the excipients lactose, D-mannitol, microcrystalline cellulose, low-substituted hydroxypropyl-cellulose, magnesium stearate, and light anhydrous silicic acid. The quality and safety of pharmaceutical products can be significantly affected by the presence of formaldehyde. The literature [31] emphasizes that the IMD excipient is produced from the condensation of allantoin with formaldehyde. This study suggests that the IMD—when associated with HQ—releases formaldehyde, thus promoting these marked changes in the physicochemical characteristics of HQ, which in turn affect the quality and safety of semi-solid pharmaceutical formulations containing this depigmenting agent. Therefore, it is recommended that the

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IMD excipient be replaced by another preservative system in formulations containing HQ.

Conclusions The results of the present study confirmed the utility and reliability of thermoanalytical analysis at the earliest stage of pre-formulation studies as a valuable tool for a rapid screening of a wide range of candidate excipients, allowing a rapid evaluation of possible drug–excipient interactions. No evidence of interaction was observed between HQ and excipients CA, CTA, EDTA, and DCO. However, based on the thermoanalytical results alone, a physical interaction was suspected between HQ and excipients DPG, GLY, HPMC, IMD, MTP, and PPP. The results of the FTIR studies of the HQ and its mixture with excipient IMD, at room temperature and heated at 190 °C, were consistent with TA experiments, where a chemical interaction between HQ and IMD was observed. For excipients DPG, GLY, HPMC, MTP, and PPP, there were no chemical interactions with HQ at room temperature; however, it can be said that the heating at 190 °C provides the appearance of a chemical interaction between HQ and HPMC. The chemometric methodology, Pearson’s correlation, based on the quantitative analysis of FTIR spectra showed that the IMD was the excipient that mostly deviated from the ideal correlation (r = 1.00). The results of the XRD of mixtures between HQ and excipients DPG, GLY, HPMC, IMD, MTP, and PPP at room temperature show that the important diffraction peaks of HQ alone, remain practically unchanged in these BM. However, the heating at 190 °C changes the crystallinity of the HQ for the mixtures with excipients DPG, HPMC, IMD, MTP, and PPP, thus indicates that no interaction occurs between these substances at room temperature, but the heating modifies the crystallinity of the HQ. In the present study, the interactions suggested were mainly observed in the results obtained by thermal techniques, but in the HQ/IMD mixture, both by thermal as the non-thermal techniques, it was observed interaction between these components. Therefore, it is recommended to replace the excipient IMD by another preservative system in semi-solid pharmaceutical formulations containing HQ. Acknowledgements The authors thank Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq), Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de Nı´vel Superior (CAPES), and Fundac¸a˜o de Apoio a` Pesquisa do Estado do Rio Grande do Norte (FAPERN).

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