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ArticleTitle Tracking of the behaviour of lidocaine basis containing hydroxypropylcellulose free films with thermoanalytical method

Article Sub-Title

Article CopyRight Akadémiai Kiadó, Budapest, Hungary

(This will be the copyright line in the final PDF) Journal Name Journal of Thermal Analysis and Calorimetry

Corresponding Author Family Name Regdon

Particle

Given Name Géza

Suffix Jr.

Division Department of Pharmaceutical Technology Organization University of Szeged

Address Eötvös utca 6, 6720, Szeged, Hungary

Email geza.regdon@pharm.u-szeged.hu

Author Family Name Gottnek

Particle

Given Name Mihály

Suffix

Division Department of Pharmaceutical Technology Organization University of Szeged

Address Eötvös utca 6, 6720, Szeged, Hungary Email

Author Family Name Pintye-Hódi

Particle

Given Name Klára

Suffix

Division Department of Pharmaceutical Technology Organization University of Szeged

Address Eötvös utca 6, 6720, Szeged, Hungary Email

Schedule

Received 19 November 2014

Revised

Accepted 6 January 2015

Abstract The excipients proved to exert strong effects on the physicochemical properties of the tested systems, and it is very important to study them intensively in preformulation studies in pharmaceutical technology. In our earlier paper, we already described the structure of Klucel-containing films with various

physicochemical examinations (tensile strength, surface properties and positron annihilation lifetime spectroscopy). The aim of our present investigations was to study the thermal behaviour of the film- forming polymers with two different chain lengths, of the taste-enhancing and plasticizing excipients and also of the films prepared from them. The thermal behaviour of Klucel LF and Klucel MF film-forming

of the polymer molecules. Among the active ingredients and excipients used, glycerol had the smallest while xylitol showed the greatest thermal stability. The shape of the TG curves shows that the decomposition process changes with the increase in the concentration of the excipients. The TG curves open up more, which is probably due to the fact that the molecules built-in among the polymer chains loosen the structure, which in turn is decomposed more easily. The TG–MS examinations revealed that during decomposition, carbon dioxide was formed in the highest concentration and that acetic acid, isopropyl alcohol and acetone also developed. The shape of the TG curves shows that in the case of the 5 and 10 % systems, the presence of lidocaine did not result in a significant difference in thermal stability.

Keywords (separated by '-') Hydroxypropylcellulose - Klucel^® LF - Klucel^® MF - Xylitol - Glycerol - Lidocaine - Free films - DSC - TG–MS

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3

Tracking of the behaviour of lidocaine basis containing

4

hydroxypropylcellulose free films with thermoanalytical method

5 Miha´ly Gottnek^•Kla´ra Pintye-Ho´di^• 6 Ge´za Regdon Jr.

7 Received: 19 November 2014 / Accepted: 6 January 2015 8 ÓAkade´miai Kiado´, Budapest, Hungary 2015

9 Abstract The excipients proved to exert strong effects on 10 the physicochemical properties of the tested systems, and it 11 is very important to study them intensively in preformu- 12 lation studies in pharmaceutical technology. In our earlier 13 paper, we already described the structure of Klucel-con- 14 taining films with various physicochemical examinations 15 (tensile strength, surface properties and positron annihila- 16 tion lifetime spectroscopy). The aim of our present inves- 17 tigations was to study the thermal behaviour of the film- 18 forming polymers with two different chain lengths, of the 19 taste-enhancing and plasticizing excipients and also of the 20 films prepared from them. The thermal behaviour of Klucel 21 LF and Klucel MF film-forming polymers was found to 22 differ only in the range of 340–400°C, which is due to the 23 different chain lengths of the polymer molecules. Among 24 the active ingredients and excipients used, glycerol had the 25 smallest while xylitol showed the greatest thermal stability.

26 The shape of the TG curves shows that the decomposition 27 process changes with the increase in the concentration of 28 the excipients. The TG curves open up more, which is 29 probably due to the fact that the molecules built-in among 30 the polymer chains loosen the structure, which in turn is 31 decomposed more easily. The TG–MS examinations 32 revealed that during decomposition, carbon dioxide was 33 formed in the highest concentration and that acetic acid, 34 isopropyl alcohol and acetone also developed. The shape of 35 the TG curves shows that in the case of the 5 and 10 % 36 systems, the presence of lidocaine did not result in a sig- 37 nificant difference in thermal stability.

38

Keywords HydroxypropylcelluloseKlucel^ÒLF 39 Klucel^ÒMF XylitolGlycerolLidocaineFree films 40 DSCTG–MS 41

Introduction 42

Differential scanning calorimetry (DSC) is a widely used 43 method to determine different properties of pharmaceuti- 44 cals: glass transition in polymers (T_g) [1–5]; amorphicity 45 and crystallinity [1,6–9]; polymorphism [1,10–14]; drug 46 solubility in polymers [1, 15–18]; characterization of 47 polymers and bio-polymers [1,19–22]; and pharmaceutical 48 dosage forms [23,24]. Thermogravimetry (TG) is also used 49 to characterize pharmaceuticals [18,25–31]. 50

Innovative pharmaceutical production has recently 51 placed great emphasis on developing drug-containing bio- 52 adhesive films. In line with this, many of the increasing 53 number of papers published in the literature report the 54 investigation of thermal behaviour. 55

A novel organic–inorganic hybrid transdermal film- 56 forming system was designed by a modified poly(vinyl 57 alcohol) (PVA) gel plasticized with glycerol (GLY), using 58 c-(glycidyloxypropyl)trimethoxysilane (GPTMS) as an 59 inorganic-modifying agent, and poly(N-vinyl pyrrolidone) 60 (PVP) as a tackifier. DSC was used to determinate the 61 thermal behaviour of the samples. The system was first 62 heated at a rate of 10°C min^-1from 20 to 200 °C and kept 63 there for 10 min then cooled down to 50°C at a rate of 64 20°C min^-1. The second heating scan from 50 to 200°C 65 at 10°C min^-1was applied to determinate the glass tran- 66 sition temperature. It was found that all PVA–GPTMS– 67 PVP–GLY samples exhibit the soft–hard segment micro- 68 phase separation. The good skin adhesive properties of the 69 films come from the flexible soft segments composed of 70 A1 M. GottnekK. Pintye-Ho´diG. Regdon Jr. (&)

A2 Department of Pharmaceutical Technology, University of A3 Szeged, Eo¨tvo¨s utca 6, Szeged 6720, Hungary

A4 e-mail: geza.regdon@pharm.u-szeged.hu

AQ1

AQ2

J Therm Anal Calorim

DOI 10.1007/s10973-015-4407-5

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71 uncross-linked PVA chain, PVP and GLY, which influ- 72 enced the viscoelastic properties and low-temperature 73 performance of the films. The hard segments (PVA–

74 GPTMS and self-cross-linked GPTMS) give the mechani- 75 cal strength and appropriate film-forming properties to the 76 system [32].

77 For transdermal controlled drug delivery, a flurbiprofen 78 (FB)–inorganic nanohybrid system was made. TG–DTA 79 was used to investigate the samples; the temperature was 80 increased from ambient to 800°C at a heating rate of 81 2°C min^-1 under 100 ml min^-1 airflow. The TG–DTA 82 was used on the dry powder. Three mass losses were 83 detected. The first mass loss of 6.51 % with a weak 84 endothermic response at around 71.9°C originated from 85 the removal of absorbed water from the surface of the 86 system. The second mass loss, approximately 8.03 % with 87 an endothermic peak at around 166.26°C, was connected 88 to the dehydration of co-intercalated water in samples. The 89 third mass loss around 47.06 % was associated with an 90 exothermic reaction in the range from 225 to 520°C [33].

91 Ibuprofen (IBU) mucoadhesive tablets containing 92 chitosan and its half-acetylated derivative as excipients 93 were compared. Polymer–IBU interactions and the degree 94 of IBU crystallinity were investigated by DSC. Samples 95 were heated under a nitrogen atmosphere at 5°C min^-1 96 from 25 to 90°C. DSC was used to determine the effect of 97 co-grinding and chitosan on IBU crystallinity. The onset of 98 IBU melting was observed at 73.9°C, and the enthalpy 99 was 125.4 J g^-1. In the co-ground mixture with chitosan, 100 IBU’s onset melting point decreased by approximately 101 3°C and the enthalpy was 121.6 J g^-1 of IBU. Chitosan 102 did not show any thermal changes over this temperature 103 range. The decreased enthalpy on co-grinding equates to a 104 4 % loss in IBU crystallinity [34].

105 Matrix-type mucoadhesive tablet from a mixture of hard 106 fat, ethylcellulose and polyethylene glycol, containing 107 indomethacin, was developed. The thermal behaviour of 108 matrix bases was investigated with DSC. Samples were 109 heated at a rate of 10°C min^-1from 20 to 170°C in air. In 110 the DSC curve, an endothermic peak was observed at 111 approximately 150°C [35].

112 Development of novel mucoadhesive pellets containing 113 valsartan (VAL) was the goal of a study of Caoa et al.

114 Two types of drug-loaded core pellets were prepared by 115 different technology, namely extrusion/spheronization 116 method. Pellets were dry-coated with a mixture of 117 hydroxypropylmethylcellulose and carbomer at different 118 ratios. The thermal properties of VAL, Povidone^Ò K30, 119 Poloxamer, Avicel^Ò PH 101, NaOH and core pellet 120 powders (F1 and F2) were determined with DSC. The 121 samples were heated from 25 to 200°C at a heating rate 122 of 10°C min^-1under nitrogen atmosphere. A broad sin- 123 gle endothermic peak was found in case of pure VAL,

while no melting peak was detected in the cases of both 124 F1 and F2 pellets. This phenomenon confirmed that there 125 was some impact between VAL and additives during 126 extrusion process [36]. 127

Pressure-sensitive IBU-containing adhesive was inves- 128 tigated by DSC. Samples were heated from 130 to 100°C 129 at a heating rate of 10 K min^-1under nitrogen atmosphere. 130 The second heating runs were evaluated. It was found that 131 IBU increasing in the formulation caused the decrease in 132 the T_g, which phenomenon was connected to the plastici- 133 zation effect of IBU on the product [37]. 134

A hydrophobic mucoadhesive thiolated chitosan for 135 pipirine (PIP) delivery was designed. The thermal degra- 136 dation behaviour of the samples was determined with TG. 137 The mass loss curves were recorded with a heating rate of 138 25°C min^-1under nitrogen flow from 50 to 600°C. For 139 chitosan, the highest thermal decomposition stage occurred 140 at 326°C with a mass loss of 41.8 %. The TG curves of 141 PIP revealed the highest thermal decomposition occurred at 142 363 °C. The chitosan–PIP microparticles curve showed a 143 maximum decomposition rate at 293°C, which was lower 144 than the pure chitosan and may indicate a lower thermal 145 stability of the PIP–chitosan microspheres than the chito- 146 san ones [38]. 147

Buccal poly(ethylene oxide) (PEO) film with (2- 148 hydroxypropyl)-b-cyclodextrin (CD) was evaluated. Films 149 were prepared at different PEO/CD ratios. The degree of 150 crystallinity was determined by DSC. The degree of crys- 151 tallinity was roughly constant for platform with a CD 152 content B60 % w/w. On the other hand, PEO/CD75 and 153 PEO/CD80 platforms showed a drastic decrease in the 154 degree of crystallinity [39]. 155

Novel sildenafil citrate (SC)-loaded PVA-polyethylene 156 glycol (PEG) graft copolymer (Kollicoat1 IR)-based orally 157 dissolving films (ODFs) were designed. The thermal 158 properties and physicochemical behaviour of samples were 159 evaluated using DSC. Kollicoat1 IR, sodium alginate 160 (ALG-Na) and glycerol were combined. The films were 161 heated at a rate of 10°C min^-1from 10 to 250°C under 162 nitrogen flow. A sharp endothermic peak of SC was found 163 at 198 °C, which was connected to the melting point of SC 164 [40]. Melting SC peak was not detected in the curves of 165 SC-loaded ODF. This indicated that interactions between 166 SC and excipients had occurred in the preparation process 167 of the film [40]. 168

The goal of a study was to investigate the potential of 169 isothermal calorimetry to monitor and characterize crys- 170 tallization in indomethacin (IND)-loaded fast-dissolving 171 PVP oral films. Subsequent analysis of the crystals with 172 DSC was made. Samples were heated from 25 to 190 °C at 173 200 °C min^-1 with nitrogen flow. It was found that iso- 174 thermal calorimetry is able to monitor IND crystallization 175 in polymer films [41]. 176

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177 Lidocaine (LID)-loaded mucoadhesive buccal patches 178 for controlled release in different formulations were stud- 179 ied. Films were loaded with LID–Compritol solid disper- 180 sion in the form of microspheres, and the effects of the 181 composition were evaluated by DSC. Samples were heated 182 at a rate of 10°C min^-1between 30 and 300°C. Melting 183 points at 82°C for lidocaine and at 75°C for the main 184 peak of Compritol were found. An irregularly shaped 185 melting endotherm main peak at 73°C was found for the 186 microsphere samples. It suggested that the solid ‘‘micro- 187 sphere’’ system was heterogeneous in nature [42].

188 Enrofloxacin (ENR)-loaded PVP thin films were for- 189 mulated for enhanced drug delivery and were evaluated 190 using DSC. Samples were heated from 25 to 300°C with a 191 heating rate of 10°C min^-1 in argon atmosphere. An 192 endothermic peak of ENR was found at 222°C corre- 193 sponding to the melting point of the drug. A large endo- 194 thermic peak of ENR–PVP at 94.57°C was found. The 195 absence/reduction in ENR peaks suggested that the drug is 196 amorphous. The result indicated that there was good 197 compatibility between ENR and PVP [43].

198 The excipients proved to exert strong effects on the 199 physicochemical properties of the tested systems, and it is 200 very important to study them intensively in preformulation 201 studies in pharmaceutical technology. For this reason, in 202 our earlier paper, we already reported our various physi- 203 cochemical examinations with Klucel-containing films 204 (tensile strength, surface properties and the measurement of 205 the free volume with positron annihilation lifetime spec- 206 troscopy), which were performed to study and to describe 207 the resulting film structure [44].

208 The aim of our present investigations was to study the 209 thermal behaviour of the film-forming polymers with two 210 different chain lengths, of the taste-enhancing and plasti- 211 cizing excipients and also of the films prepared from them, 212 as these data can provide useful information on the storage 213 conditions and stability of drug-containing films.

214 Materials

215 HPC (Klucel MF and LF) (Aqualon; Hercules Inc., Wil- 216 mington, USA.) was used as a film-forming polymer. The 217 main differences between the two Klucel products are in 218 the molecular mass and the viscosity of the solution. MF 219 has a higher viscosity in solution and a higher molecular 220 mass. HPC is a non-ionic, water-soluble cellulose ether, 221 and its films are appropriately flexible even without any 222 plasticizer.

223 The local anaesthetic lidocaine basis (Lid) (Ph. Eur., 224 Societa` Italiana Medicinali Scandicci, Firenze, Italy) was 225 chosen as the active ingredient. Xylitol (Xyl) (Ph.Eur.,

227 Roquette, Lestrem, France) was used as the taste improver. 227 Glycerol (Gly) (Ph. Eur., Molar Chemicals Kft., Budapest, 228 Hungary) was used as a plasticizer, and in films it can act 229 as a taste coverer. 230

Methods 231

Preparation of free films 232

The optimum polymer concentration was first established, 233 2 % w/w solutions were chosen for both types of Klucel as 234 we wished to compare their physicochemical properties. 235 Lidocaine (Lid) was grounded in a mill (Retsch RM 100, 236 Retsch GmbH, Haan, Germany), and the 100–200-lm 237 powder fraction was incorporated into the solution. Xylit 238 (Xyl) dissolved readily, and glycerol (Gly) compounded 239 well in the water–polymer mixture. Lid, Gly and Xyl were 240 all used in the same concentration (5, 10 or 15 % w/w of 241 the film-forming polymer). Samples were poured onto a 242 non-stick surface. All the films were made by the same 243 solvent-casting technology and stored at room temperature 244 (25°C/65 % RH) for a day and then placed into a climate 245 chamber for 24 h (40 °C/50 % RH). 246

Thermoanalytical measurements 247

The thermoanalytical examinations of the materials were 248 carried out with a Mettler Toledo TG/DSC1 instrument 249 (Mettler Toledo, Switzerland). During the DSC measure- 250 ments, the start temperature was-40°C, the end temper- 251 ature was 300°C, and the applied heating rate was 252 10°C min^-1. Argon atmosphere was used, and nitrogen 253 was used as drying gas. 10±1-mg sample was measured 254 into an aluminium pan (40ll). The curves were calculated 255 from the average of three parallel measurements and were 256 evaluated with STARe software. 257

For the TG and the DSC measurements, the start tem- 258 perature was?25°C, the end temperature was 400°C, and 259 the applied heating rate was 10°C min^-1. Nitrogen 260 atmosphere was used. 10±1-mg sample was measured 261 into an aluminium pan (100ll). The curves were calcu- 262 lated from the average of three parallel measurements and 263 were evaluated with STARe Software. 264

The thermal characteristics of the sample mass loss were 265 determined with a thermal gravimetric analyzer (Mettler 266 Toledo, model TG/DSC1) coupled with a quadrupole mass 267 spectrometer (Pfeiffer Vacuum, model Thermostar^TMGSD 268 320), operated under N2atmosphere (purity=99.999 %, 269 70 ml min^-1 flow rate). The connection between the TG 270 and the mass spectrometer was made by means of a silica 271 capillary, which was maintained at 120 °C. 272

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273 Results and discussion

274 The thermal studies were started by studying the film- 275 forming polymers as well as the active ingredient and ex- 276 cipients to be used, and the changes were monitored 277 between 25 and 400°C at a constant heating rate. The 278 changes in heat flow were followed with the help of DSC 279 curves. The thermal behaviour of the two film-forming 280 polymers, lidocaine used as an active ingredient and the 281 two excipients (glycerol and xylitol) is shown in Fig.1.

282 A slight endothermic baseline shift can be observed in 283 the DSC curves of the Klucel^Ò LF and MF polymers 284 between 40 and 100°C, which can be explained with the 285 removal of the water content of the polymer. The heat flow 286 curves show no difference until 340°C, and then signs of 287 decomposition appear in both curves.

288 The DSC curve of glycerol shows a definite endothermic 289 peak between 50 and 150°C due to the higher water 290 content, while at about 200°C signs of decomposition can 291 be observed until 300°C.

292 In the DSC curve of xylitol, an onset value of 92.2°C is 293 followed by a peak melting point at 95.6°C. The enthalpy 294 change of the process is 217.4 J g^-1. Xylitol has much 295 greater thermal stability as the baseline change and the 296 decomposition process start only at about 280°C and end 297 over 380°C.

298 Lidocaine, which is used as an active ingredient, has a 299 lower melting point than the excipients because the onset 300 value is 67.2°C and the peak of the melting point appears 301 at 68.6°C. The enthalpy change of the process is 302 59.1 J g^-1. The baseline change appears over 180 °C, and 303 then the decomposition process is accelerated over 200°C 304 and finishes at about 330°C.

The TG curves of the same materials in Fig.2show that 305 the two different film-forming materials are thermally 306 stable, a mass loss of only 1–1.5 % can be detected until 307 100 °C, the decomposition process starts over 300°C, and 308 mass loss is 85 % for Klucel LF and 87 % for Klucel MF 309 until 400°C. However, the rate of the decomposition 310 process is different, and it is faster for the LF product and 311 slower for the MF product, which is also shown clearly by 312 the numerical data of the mass loss of the two polymers 313 (see Table 1). 314

From the data, it can be stated that the mass loss of 315 1.0–1.5 % observed at the beginning of heating can be 316 explained by the removal of water from the film, and then 317 further mass loss starts only at about 300 °C. The thermal 318 behaviour of the two polymers differs significantly between 319 340 and 400°C, which can be explained by the different 320 chain lengths of the two polymers. The Klucel^Ò MF 321 product with a longer chain has greater thermal stability, 322 and probably the more stable structure is broken only at 323 higher temperatures. 324

The thermal behaviour of the excipients as shown by 325 their TG curves (see Fig.2) can be described well, and it 326 confirms the information obtained from the DSC curves. 327 Although both excipients were entirely decomposed by the 328 end of the examination, considerable differences can be 329 observed in their behaviour. Xylitol proved to be the most 330 stable as the decomposition process really starts only over 331 300 °C. Ensuing from its material properties, glycerol first 332 loses its water content at the beginning of heating, and then 333 its decomposition starts over 180°C and finishes at 334 290 °C. The thermal behaviour of the active ingredient is 335 somewhere between those of the two excipients, as in the 336 case of lidocaine, the mass loss curve reveals that 337 decomposition starts at about 180–200°C (see Table1.). 338

40 Lidocaine Xylitol Glycerol Klucel MF Klucel LF

Heat flow/W g^–1

^exo

60 5 W g^–1

80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 Temperature/°C

Fig. 1 Thermal properties of Klucel^Òfilm-forming materials, active ingredient and excipients as shown by the DSC curves

40 Mass/%

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 Temperature/°C Glycerol Lidocaine Xylitol

MF 87.4 % LF

85.2 %

97.6 % 100.6 % 99.4 % 50

%

Fig. 2 Thermal properties of Klucel^Òfilm-forming materials, active ingredient and excipients as shown by the TG curves

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After studying and learning about the thermal behaviour 339 of the film-forming polymer and the excipients to be used, 340 we wished to study the behaviour of the free films which 341 were prepared from them and contained both excipient and 342 active ingredient. As regards Klucel LF and MF products, 343 differences in thermal stability were observed only over 344 300°C, so they behaved in the same way when applied 345 under the conditions of the oral mucosa. Klucel LF pro- 346 ducts were chosen for the formulation of bioadhesive films 347 and the examination of their thermal stability, and these 348 results are presented in this paper. 349

The thermal behaviour of Klucel^ÒLF films containing 350 both xylitol and glycerol is illustrated in Fig.3. 351

Glycerol and xylitol were present in the films in the 352 same concentrations (at 0–5–10–15 % w/w of the poly- 353 mer). The shape of the TG curves shows that although the 354

Table1Masschangeofvariousexcipientsandtheactiveingredientasafunctionoftemperature SampleMassloss/% 100°C180°C250°C300°C320°C340°C360°C380°C400°C KlucelLF1.13±0.011.13±0.011.47±0.012.72±0.014.55±0.038.43±0.1318.42±0.5955.64±0.8185.2±1.430 KlucelMF1.51±0.321.81±0.432.42±0.26533.28±0.264.10±0.886.42±1.1914.1±1.7050.5±2.1287.4±1.2653 Glycerol4.99±1.9815.7±5.0431.4±9.9098.9±4.3099.3±3.6699.4±3.6799.4±3.6799.4±3.6799.4±3.67 Xylitol0.13±0.020.39±0.181.22±0.476.26±0.2714.38±0.1635.3±0.0578.7±0.35100.9±1.34101.4±1.49 Lidocaine0.21±0.010.04±0.017.39±0.7645.4±4.2197.6±5.69100.6±1.52100.6±1.54100.6±1.54100.6±1.55

40 60 Mass/%

80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 Temperature/°C 50

%

15 % Xylitol 15 % Glycerol 10 % Xylitol

10 % Glycerol 5 % Xylitol

5 % Glycerol

Klucel LF

Fig. 3 Thermal properties of films made from Klucel^Ò LF film- forming material containing xylitol and glycerol as shown by the TG curves

40 Mass/%

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 Temperature/°C 50

% Glycerol

99.4 % Lidocaine

100.6 %

Xylitol 15 % 10 % 5 %

Klucel MF Klucel LF

97.6 %

Fig. 4 Thermal properties of films made from Klucel^Ò LF film- forming material containing lidocaine as well as xylitol and glycerol as shown by the TG curves

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355 decomposition process changes with the increase in the 356 concentration of the excipients, when heated up to 400°C, 357 mass loss does not differ significantly compared to Klucel^Ò 358 LF films without excipients. At the beginning of heat 359 treatment, mass loss can be explained by the removal of the 360 water content in every case and it is proportional to the 361 concentration of glycerol. However, over 180–200°C, the 362 decomposition processes start, and the TG curves open up 363 more, which is probably due to the fact that the molecules 364 built-in among the polymer chains loosen the structure, 365 which in turn is decomposed more easily.

366 Then, we studied the thermal behaviour of drug-con- 367 taining films. In Fig.4, the thermal behaviour of Klucel^Ò

LF films containing lidocaine as well xylitol and glycerol is 368 presented. The effect of the ratio (quantity) of the com- 369 ponents on the shape of the TG curves as well as on the 370 quantity and disproportion of the arising mass loss can be 371 seen clearly. It is remarkable that while a smaller mass loss 372 was observed for the 5 and 10 % films, the mass loss of the 373 15 % film was greater, which can be explained by the 374 loosening effect of glycerol and lidocaine on the polymer 375 structure. 376

The concentrations of the active ingredient and the ex- 377 cipients in the films were always the same (0–5–10–15 % 378 w/w of the film-forming polymer). The shape of the TG 379 curves is similar to the one shown by films without lido- 380 caine, but they can be compared really well if the TG 381 curves of films with lidocaine (continuous line) and with- 382 out lidocaine (broken line) are plotted together (see Fig.5). 383 The temperature range (200–400°C) of the greatest 384 importance with respect to the phenomenon is focussed on 385 here. The shape of the curves shows that in the case of the 5 386 and 10 % systems, the presence of lidocaine practically did 387 not result in a significant difference in thermal stability, 388 while in the concentration of 15 %, the films which con- 389 tained lidocaine were decomposed more easily, which is 390 due to the greater quantity of the materials used and to the 391 ensuing looser structure. 392

This can probably be explained by the fact that the 393 plasticizer, when used in a lower concentration, can be 394 incorporated into the film structure, which we have already 395 confirmed in the case of Metolose free films [45–47]. 396 However, when it is applied in higher concentrations, the 397

200 210 50

%

220 Mass/%

230 240 250 260 270 Without lidocaine With lidocaine

280 290 300 310 320 330 15 % 10 % 5 %

340 350 360 370 380 390 Temperature/°C

Fig. 5 Comparison of the thermal properties of xylitol and glycerol containing Klucel^ÒLF films with and without lidocaine between 200 and 400°C as shown by the TG curves

40 50

% Mass/%

2

10^–5 10^–4 10^–3 10^–2 10^–1 10⁰ nA

^exo

4 6 8 10

18

12 14 16 18 20 22 24 26 28 30 32 34

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 Temperature/°C

Time/min

42 43

41 45

44

58 Fig. 6 Thermal properties of

films made from Klucel^ÒLF film-forming material containing 15 % glycerol as shown by the TG–MS curves

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398 stability of the film structure deteriorates, which is illus- 399 trated well by the presented curves, when 15 % of other 400 components were used besides the polymer.

401 We also performed the TG–MS examination of all the 402 films, we analysed the evolved gases with a mass spectro- 403 graph coupled with the TG in order to obtain information 404 about the stability of the film structure. Among the several 405 measurements, the data obtained with films containing 15 % 406 glycerol are presented in Fig.6. Although no change can be 407 observed for the m/z=18 fragment on axis ‘‘Y’’ with a 408 logarithmic scale, in the case of an absolute scale water 409 removal can be seen between both 40–150 and 350–400°C, 410 and with the start of decomposition, a concentration increase 411 was experienced for further fragments (m/z=41, 42, 43, 44, 412 45 and 58), starting practically at the same time. The peak 413 intensity of the fragments depicted decreased in the fol- 414 lowing order:m/z=44–43–42–41–58–45. All these indi- 415 cate that carbon dioxide is formed in the greatest 416 concentration, which is confirmed by the increase of m/ 417 z=44. m/z=43, 45 may indicate the development of 418 acetic acid and/or isopropyl alcohol, while m/z=43, 58 419 may be indicative of the formation of acetone.

420 Conclusions

421 In the course of our experiments, free films were prepared 422 from Klucel film-forming materials with various chain 423 lengths for buccal administration, with glycerol and/or 424 xylitol taste enhancer excipient and lidocaine active 425 ingredient incorporated in various concentrations. During 426 the study of the bioadhesive films, it was found that the 427 thermal behaviour of Klucel LF and Klucel MF film- 428 forming polymers was different from each other only in the 429 temperature range of 340–400°C, which is due to the 430 difference in the chain length of the polymer molecule.

431 Among the active ingredients and excipients used, 432 glycerol proved to be the least stable thermally, while 433 xylitol was the most stable. The shape of the TG curves 434 shows that the decomposition process changes with the 435 increase in the concentration of the excipients. In the case 436 of glycerol, the decomposition processes start over 437 180–200°C, and the TG curves open up more, which is 438 probably due to the fact that the molecules built-in among 439 the polymer chains loosen the structure, which in turn is 440 decomposed more easily.

441 The role of the active ingredient lidocaine in thermal 442 stability was also examined, and it was found that the shape 443 of the curves shows that in the case of the 5 and 10 % 444 systems, the presence of lidocaine did not result in a sig- 445 nificant difference in thermal stability, while in the con- 446 centration of 15 %, the films which contained lidocaine 447 were decomposed more easily, which is due to the greater

quantity of the materials used and to the ensuing looser 448 structure. 449

The TG–MS examinations revealed that with the start of 450 decomposition, a concentration increase was seen in the 451 case ofm/z=41, 42, 43, 44, 45 and 58 fragments, starting 452 practically at the same time. The peak intensity of the 453 fragments in the highest concentration may indicate the 454 formation of carbon dioxide and also the development of 455 acetic acid, isopropyl alcohol and acetone. 456

As a summary, it can be stated that the thermal stability 457 of free films prepared from Klucel LF polymer is appro- 458 priate, and in the case of the 5 and 10 % systems, the 459 presence of lidocaine did not result in a significant differ- 460 ence in thermal stability. The results not only help to 461 choose the formulation conditions but also provide useful 462 information concerning the packaging and storage condi- 463 tions as well as the stability of the final product. 464

Acknowledgements The publication is supported by the European 465 Union and co-funded by the European Social Fund. Project number: 466 TA´ MOP-4.2.2.A-11/1/KONV-2012-0047. 467

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