ARTICLE pubs.acs.org/JPCC
Characterization of Latent Heat-Releasing Phase Change Materials for Dermal Therapies D. G. Wood,†,§ M. B. Brown,‡,§ S. A. Jones,† and D. Murnane*,†,‡,^ †
Pharmaceutical Science Division, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, England School of Pharmacy, University of Hertfordshire, College Lane, Hatfield, Herts, AL10 9AB, England § MedPharm Ltd., Unit 3/Chancellor Court, 50 Occam Road, Surrey Research Park, Guildford, Surrey, GU2 7YN, England ‡
bS Supporting Information ABSTRACT: Phase change materials (PCMs) have been developed as heat storage solutions, particularly for the supply of “green” energy. One interesting use of PCMs is long-term energy storage, in which a phase transition is triggered externally. In addition, PCMs are a potential method of administering heat for therapeutic purposes (therapeutic hyperthermia). This exciting therapeutic intervention provides an adjunct to chemotherapy and the potential to improve drug absorption. The purpose of this study was to characterize and control the heat generation process from supercooled salt PCMs. Salts were selected on the basis of their lack of toxicity and previous use in medicine. The crystallization of sodium formate, acetate (SA), and thiosulfate (ST) was characterized and monitored for heat generation. Only SA and ST had the wide metastable limits and exothermic crystallization appropriate for safe dermal hyperthermia (3250 C). The crystallization rate, heating profile, and heat capacities (Cp) of the PCM and dry crystals at different supersaturation levels (high (H) and low (L)) were determined. A low degree of supersaturation produced lower maximum temperatures (e.g., SAH Tmax = 55.7 ( 0.3 C, SAL Tmax = 39.1 ( 0.3 C), whereas low crystallization rates provide prolonged hyperthermia (e.g., STH DUR 1125 s). The heat release profiles can be optimized for therapeutic applications by controlling the following variables: (1) mass of salt which crystallizes (enthalpy released), (2) rate of crystallization, and (3) relative heat capacities of the supercooled solution and crystalline material. As an example, therapeutically relevant hyperthermia increased lidocaine flux across a model skin membrane from 7.18 ( 1.8 to 33.7 ( 2.6 μg cm2. The current study has characterized the thermogenesis from pharmaceutically acceptable materials and provides for the development of PCMs as reliable, effective, and therapy-specific heat administration systems.
1. INTRODUCTION Renewable energy storage systems have received widespread attention over the last 30 years. Latent heat is a useful storage mechanism due to the high energy storage density it can provide.1 Materials with large latent heats of transformation and high thermal conductivity are employed as phase change materials (PCMs) for the storage and release of heat. Inorganic salt hydrates and salt solutions are a particularly efficient class of PCMs due to their high latent heats of fusion and small volume changes on melting.2 For example, sodium acetate trihydrate (SAT, NaCH3COO 3 3H2O) and sodium thiosulfate pentahydrate (STP, Na2S2O3 3 5H2O) are highly suitable PCMs due to their large latent heats of fusion, 264 and 201 kJ kg1 respectively.3,4 Thermal energy storage is being developed for applications such as heat recovery to avoid waste in power plants and to level energy supply between peak and off-peak periods.1,5 Latent heat storage materials (i.e., PCMs) absorb and release heat at a nearly constant temperature associated with solidliquid (melting) or liquidsolid (recrystallization/solidification) phase transformations. Energy is r 2011 American Chemical Society
absorbed by materials, providing the heat of fusion and later released during recrystallization, enabling thermal cycling. Supercooled salt hydrate solutions are produced by dissolving the salt in water with the aid of heat. The water of solution may be created upon melting of the salt hydrate and liberation of the water of hydration (incongruent and semicongruent dissolution). Removal of heat leads to (re)crystallization of the salt hydrate and recovery of the latent energy of crystallization. Many salt hydrates display supercooling during which, upon cooling, the salt passes the melting point of the salt hydrate but does not crystallize.6 Supercooling represents a disadvantage for thermal energy storage systems by lowering the enthalpy recovery upon the eventual onset of crystallization.7 Supercooling systems require seeding to induce crystallization at the phase transition temperature. The practical application of salt hydrate PCMs for thermal energy cycling is difficult due to the requirement for reproducible and Received: October 4, 2010 Revised: March 22, 2011 Published: April 07, 2011 8369
dx.doi.org/10.1021/jp109518k | J. Phys. Chem. C 2011, 115, 8369–8375
The Journal of Physical Chemistry C consistent seeding. However, because supercooled salt hydrates form metastable liquids (whereby only external induction of nucleation initiates crystallization and heat release), they do provide the opportunity for triggered heat release. The excellent ability to store heat, high thermal conductivity, and low price1 coupled with the ability to remain stable in the supercooled state for years7 makes supercooled salt systems a possibility for several commercial applications. The use of heat in medicine (therapeutic hyperthermia) emerged in the 1970s. Cells that are least sensitive to radiation- and chemotherapy are most sensitive to the effects of locally induced hyperthermia.8 Many modalities of heat application have been developed, with recent tissue-specific techniques focusing on alternating current magnetic fields9 and magnetic resonance technologies.8 In addition to the potential for therapy of skin malignancy, applied heat has also been shown to improve the transport of drug molecules across the epidermis (i.e., thermophoresis).10 The skin provides facile access for heating systems; however, currently, only one product is available: a patch11 that is employed to enhance the delivery of therapeutic agents across the skin. Heat is generated by the exothermic oxidation of iron, producing a maximum temperature of ∼42 C.12 The little published information on temperatures tolerated by the skin would suggest that an appropriate range for dermal hyperthermia would be up to 50 C.13 Excess heating of the skin can lead to burns and irreversible damage, such as protein denaturation. The robustness of the iron oxidation reaction has been questioned with patches drastically exceeding predicted temperatures14 leading to the possibility of irreversible skin damage. PCMs in the form of supercooled salt systems possess the potential for triggered crystallization to achieve dermal hyperthermia. Many PCMs are commercially available to achieve different heat release profiles; however, materials employed therapeutically must be biocompatible and display low toxicity. Excipient and drug delivery device component materials ideally fall into the US Food and Drug Administration categorization of the US Food and Drug Administration as generally recognized as safe (GRAS).15 The purpose of the current work was to characterize the factors controlling heat generation from GRAS-listed supercooled salt systems in an effort to develop a suitable tunable heating system to investigate further the applications of heat in topical therapy.
2. METHODS AND MATERIALS 2.1. Materials. Sodium formate, sodium thiosulfate, sodium acetate (anhydrous), potassium acetate (minimum 99%), sodium carboxymethyl cellulose (medium viscosity grade), and aluminum oxide (sapphire) (100 mesh, 99% purity) were all purchased from Sigma Aldrich (Gillingham, UK). Deionized water (HPLC grade) was supplied by Fisher Scientific (Loughborough, UK). Phosphate buffered saline tablets (0.15 M, pH 7.3) were acquired from Oxoid (Basingstoke, UK). Lidocaine base (BP) was obtained from QueMaCo Ltd. (Nottingham, UK). Silicone membrane (Folioxane C16, polydimethyl siloxane) 0.12 mm thickness was purchased from Novatech Ltd. (Cedex, France). Indium (puratronic grade) was supplied by Alfa Aesar (Johnson-Matthey (Deutschland) GmbH&CoKG), Karslruhe, Germany. 2.2. Selection of Potential Thermogenic Agents. Salts were selected for characterization that displayed the following properties: (i) GRAS-listed, (ii) form metastable solutions upon cooling, and (iii) are capable of increasing temperature above the baseline
ARTICLE
temperature of skin (32 C). Sodium salts are included in preparations for medical therapies,16,17 and those salts that are GRASapproved food additives15 were selected. Solutions of sodium acetate, sodium thiosulfate, and sodium formate were prepared by melting 10.00 g of the relevant salt in a glass vial (28 mL) in the presence of water by heating on a hot plate stirrer (Stuart Scientific, Staffordshire, UK). In total, 21 solutions of each salt were prepared by adding water in the range of 0.0020.00 g, such that each vial contained 1.00 g more water than the preceding vial. The mixtures were stirred while hot for 3 h until a visibly clear homogeneous solution was obtained. Aliquots (2.5 mL) of the salt solutions were transferred into glass vials (7 mL volume, 2.54 cm2 base surface area) and allowed to cool to room temperature after sealing, assuring a consistent volume/surface area ratio. Solutions that did not spontaneously crystallize upon cooling were induced to nucleate by the introduction of a seed crystal of their respective crystallized salt hydrate. The maximum temperature produced by the crystallizing solutions was measured by placing a wire probe connected to a thermocouple (Hanna Instruments, UK) directly into the solution. Each measurement was performed in triplicate. 2.3. Characterization of the Heat Generation Process. Two concentration levels of the supercooled solutions of sodium acetate and sodium thiosulfate were selected from the salt screen to characterize the heat generation process. Stock solutions were prepared as previously detailed in Section 2.2 with the salt (10.00 g) heated with water until molten. The high level (SAH) of sodium acetate contained 8.00 g of water, and the low level (SAL) contained 12.00 g of water. The high level of sodium thiosulfate (STH) contained 5.00 g of water, and the low level (STL) contained 8.00 g of water. 2.3.1. Crystallization Rate. Crystallization rates were determined by measuring the crystallization progress against time. A 5 mL polypropylene syringe (BD, USA) was filled with the hot salt solution then held vertically on a clamp stand. Once cool, a seed crystal was touched to the syringe opening and the time taken for the crystallization front to migrate to the specified markings spaced 1 mL apart was recorded. Times were recorded once the crystallization front was traveling down an even diameter (once past the 1 mL mark). The distance between the marks on the 5 mL syringe was 0.9 cm. The crystallization rate was converted into mm s1. 2.3.2. Identification of Salt Forms. Differential scanning calorimetry (DSC) using a TA 2920 calorimeter (TA Instruments, UK) was used to determine the crystal forms produced following crystallization and drying of the high and low concentration levels of sodium acetate and sodium thiosulfate hydrates. Prior to use, the calorimeter was calibrated according to the manufacturer’s instructions using an indium standard. Approximately 10 mg of test material was accurately weighed into 10 μL of aluminum sample pans. Both the sample pans and reference pans were sealed by cold-welding under pressure using a crimper tool (TA Instruments, UK; i.e., hermetically sealed). Sodium acetate samples were heated between 25 and 70 C; sodium thiosulfate samples were heated between 25 and 65 C. For both salts, the heating rate was 5 C min1. 2.3.3. Determination of Heat Capacities. The Cp of the crystals formed from supercooled aqueous sodium acetate and sodium thiosulfate at both high and low concentration levels were determined from the DSC experiments above. Additionally the Cp of the supercooled solutions (phase change liquids (PCLs)) were determined. PCLs were pipetted into the aluminum sample pans, accurately weighed to between 10 and 15 mg, and the pans were hermetically sealed to ensure they were airtight. PCLs were allowed to 8370
dx.doi.org/10.1021/jp109518k |J. Phys. Chem. C 2011, 115, 8369–8375
The Journal of Physical Chemistry C
ARTICLE
cool to room temperature prior to DSC analysis. Samples were heated at a rate of 5 C min1 between 20 and 60 C. Temperature and cell constant calibrations were performed at the same heating rate using an indium standard accurately weighed into hermetic aluminum pans. The heat flow signal (mW) of each sample was exported into Microsoft Excel 2007 as an ASCII file, and all measurements were performed in triplicate. Heat capacity (Cp, in J g1 K1) determinations were performed by measuring the difference in the y-axis deflection (ΔH, in mW) between a sample and blank cell upon heating, according to eq 1: 60E ΔH ð1Þ Cp ¼ Hr m where Hr is the heating rate (K min1), E is the cell heat capacity constant, and m is the mass (mg) of the sample. E was obtained by heating an accurately weighed sample of sapphire at 5 K min1 and equating the y-axis deflection between the sapphire and blank cell with the Cp values determined by Archer18 according to eq 1. The accuracy of the heat capacity measurements was determined to be (6% on the basis of the measurement of the Cp of dried sapphire (99% purity). This value was judged to be acceptable for the DSC 2920 model employed according to previous reports.19,20 On this basis, Cp determinations were performed in triplicate, as recommended.21 2.3.4. Measurement of Heating Profiles of Phase Change Materials. Glass vials (7 mL volume) were held in a plastic clamp attached to a clamp stand. The plastic clamp was used in an attempt to eliminate conductive heat loss to the surroundings. A wire probe connected to a thermocouple (Hanna Instruments, UK) was inserted into the center of the supercooled salt solution. A seed crystal was added to the vial, and the temperature was recorded over time. The maximum temperature (Tmax), time to maximum temperature (tmax), and duration (DUR) above 32 C (i.e., external surface temperature of human skin) were recorded for each supercooled salt. Each measurement was repeated in triplicate. 2.4. Investigation of Thermogenic Formulations for Drug Delivery Applications. To demonstrate a possible application of PCMs in therapeutic hyperthermia, a PCM was formulated from supercooled SAT (10.0 g of SA/10.0 g of water). The latter PCM was predicted to raise the temperature of a 2 cm diameter surface to ∼50 C (safe to the skin). Aliquots (2.5 mL) were applied to a 2.5% w/w aqueous carboxymethyl cellulose gel containing 1.5% w/v lidocaine,22 and the permeation of lidocaine across a silicone membrane into phosphate buffered saline (0.15 M, pH 7.3) was assessed using Franz-type diffusion cells. The permeation of lidocaine was determined from the cumulative mass transported across the membrane over time by assaying the concentration of lidocaine in the receiver fluid using a high performance liquid chromatography method shown to be “fit for purpose”.22
3. RESULTS 3.1. Thermogenic Salt Selection and Metastable Zone Width Determination. Three potential supercooled salt systems were
selected on the basis of their GRAS acceptance15 (sodium acetate [SA], sodium thiosulfate [ST], and sodium formate [SF]) and were assessed for their heat generation (maximum temperature (Tmax) produced, Figure 1). The temperature rise observed from SF (25.3 ( 0.3 C) was lower than the surface temperature of human skin (32 C) and does not appear in Figure 1. The boundaries of the metastable regions of the aqueous solutions of SA and ST were evaluated as a function of concentration (mole fraction, X) of the
Figure 1. Representation of the labile, metastable and stable concentration limits of supercooled solutions of sodium acetate (O) and sodium thiosulfate (0). Each point represents the maximum temperature (Tmax) produced when crystallization was induced (mean ( SD; n = 3). The vertical lines represent the boundaries of sodium acetate (dashed) and sodium thiosulfate (solid).
anhydrous salt. The widest metastable region and highest temperatures following crystallization were measured for the supercooled SA solutions. The temperature produced upon crystallization of solutions within the metastable region was found to be dependent on the concentration of the respective salts. At the maximum salt concentration in the metastable region, the Tmax of SA was 57.5 ( 0.1 C and ST was 48.6 ( 0.2 C. 3.2. Characterization of the Phase Change Materials. 3.2.1. Solid State Form of Crystallized Salts. Differential scanning calorimetry (DSC) was used to examine the crystal form of SA and ST, which crystallized at two concentration levels. The high and low concentrations for SA were SAH X = 0.22 (high) and SAL X = 0.15 (low), and for ST, were STH X = 0.19 (high) and STL X = 0.12 (low). Crystals of SA (Figure 2a) exhibited the same onset of melting (SAH: 56.3 ( 0.1 C; SAL 56.4 ( 0.1 C, n = 4) and similar melting peak temperatures (SAH: 58.2 ( 0.5 C; SAL 58.8 ( 0.6 C, n = 4). Crystals of ST (Figure 2b) were also identical (melting onset: STH: 45.9 ( 0.2 C; STL 46.2 ( 0.1 C, n = 3; melting peak: STH: 48.0 ( 0.2 C; STL 48.8 ( 0.6 C, n = 3). The melting points confirmed that the trihydrate for sodium acetate (i.e., SAT) and the pentahydrate (i.e., STP) for sodium thiosulfate were formed, in agreement with literature melting values2,5,7,23,24 for SAT (58 C) and STP (48 49 C). However, the incongruent melting observed with the isolated SAT and STP crystals did not enable the calculation of enthalpies of melting by DSC. 3.2.2. Heat Capacity Determination of Phase Change Liquids Pre- And Postcrystallization. The heat capacity of the PCLs and isolated dried crystals were derived from the measured heat flow of a minimum of three replicates using eq 1 and were plotted against temperature (Figure 3). The Cp of the dry crystals of SAH (2.4 ( 0.1 J kg1 K1) and SAL (3.0 ( 0.2 J kg1 K1) demonstrated an insignificant (p > 0.05) increase to 2.7 ( 0.3 and 3.2 ( 0.2 J kg1 K1, respectively, when the temperature was raised to 50 C. When approaching the melting point, an increase in the Cp was observed. The Cp of the crystals of SAL (∼3.0 J kg1 K1) was significantly (p e 0.05) higher over the temperature range 2545 C 8371
dx.doi.org/10.1021/jp109518k |J. Phys. Chem. C 2011, 115, 8369–8375
The Journal of Physical Chemistry C
Figure 2. Differential scanning calorimetric thermograms of (a) sodium acetate, SAH (solid) and SAL (dashed), and (b) sodium thiosulfate, STH (solid) and STL (dashed), following exothermic crystallization.
than the dry crystals of SAH (∼2.5 J kg1 K1). The Cp of the dry crystals of STH (∼2.3 J kg1 K1) was also significantly higher than that of STL (∼1.7 J kg1 K1) over the temperature range studied (p < 0.05). The Cp of the PCLs for SAH and SAL remained constant at ∼4.4 J kg1 K1 over the temperature range studied (2555 C) and were not significantly different from each other (p > 0.05). The Cp of the PCLs of SAH and SAL were both significantly (p < 0.05) higher than those of their respective dry crystals. The heat capacities of STH and STL PCLs were linear over the temperature range 2545 C. There was no significant difference (p > 0.05) between the heat capacities for the PCLs of either sodium acetate or sodium thiosulfate at any concentration level. 3.2.3. Crystallization Rate of Supercooled Salt Systems. Investigation into the crystallization rate was conducted by monitoring the crystallization front migration over time (Figure 4). The rates of crystal growth were fastest for SAH (7.28 ( 0.45 mm s1) followed by SAL (2.61 ( 0.04 mm s1), then STH (0.26 ( 0.21 mm s1), and the slowest was STL, which had a crystal growth rate of 0.16 ( 0.09 mm s1. 3.2.4. Heating Profiles of Supercooled Salt Systems. The temperature profiles of the four PCLs were recorded over a 30 min period after crystallization was initiated with a nucleating agent
ARTICLE
Figure 3. (a) The heat capacity (J kg1 K1) of the precrystallization liquor, SAH ()) and SAL (0), and crystals post-crystallization, SAH (Δ) and SAL (O), of sodium acetate at two different concentrations. (b) The heat capacity of the precrystallization liquor, STH ()) and STL (0), and crystals, post crystallization, STH (Δ) and STL (O), of sodium thiosulfate at two different saturation levels (mean ( SD, n = 3).
(Figure 5). SA systems exhibited an almost instantaneous temperature rise (tmax = 15 ( 0 s for both SAH and SAL), which was dissipated to the surroundings quickly (DUR = 725 ( 35 s for SAH and DUR = 335 ( 17 s for SAL). In contrast, the ST temperature rise was slower to peak (tmax = 140 ( 9 s for STH and tmax = 75 ( 0 s for STL), but also dissipated slowly (DUR = 1125 ( 0 s for STH and DUR = 535 ( 35 s for STL). Thus, tmax was significantly faster for SA than for ST at both concentration levels (p < 0.05), whereas at either high or low concentration level, DUR was longer for ST than SA. At the highest concentration level, the Tmax for SAH (55.7 ( 0.3 C) and STH (45.5 ( 0.2 C) were higher when compared with their respective salts at lower concentration levels SAL (39.1 ( 0.3 C) and STL (38.5 ( 0.2 C). 3.3. Application of Phase Change Materials for Dermal Therapy. On the basis of the results presented in Section 3.2.4, it was predicted that a PCM system consisting of 10.0 g of SA and 10.0 g of water would produce a short tmax characteristic of SA systems but, due to the slower crystallization rate at low supersaturation, would produce a safe Tmax and an extended DUR. The formulation (Figure 5) produced a Tmax = 51.6 ( 0.3 C and a DUR = 10.75 min with a tmax = 15 s. The hyperthermia was 8372
dx.doi.org/10.1021/jp109518k |J. Phys. Chem. C 2011, 115, 8369–8375
The Journal of Physical Chemistry C
Figure 4. Time required for the crystal front migration of sodium acetate and sodium thiosulfate at two different concentrations. Sodium acetate, high (SAH, )) and low (SAL, Δ); and sodium thiosulfate, high (STH, 0) and low (STL, O) (mean ( SD, n = 3).
ARTICLE
identification of their metastability (i.e., resistance to crystallization) or lability (i.e., spontaneous crystallization) upon cooling and their potential thermogenesis. Sodium formate (SF) was dismissed from further investigation as a consequence of not generating heat above 32 C, the baseline surface temperature of human skin. Sodium acetate and sodium thiosulfate produced systems with wide metastable limits (Figure 1). SA (crystallizing as sodium acetate trihydrate, SAT) and ST (crystallizing as sodium thiosulfate pentahydrate, STP) were found to have slightly different metastable regions (STP narrower than SAT by 0.1 mol fraction). Confirmation of the salt form identity was achieved by melting point analysis. The observation of incongruent melting at 5 C min1 as well as the difficulty in obtaining pure crystals of SAT and STP (drying techniques leading to partial dehydration) rendered the determination of enthalpies of melting to be inappropriate. The differing metastability was attributed in part to the solubilities of SAT and STP in water and also differences in their temperature-solubility curves, both of which determine the metastable limits. The solubility of STP in water at 20 C is ∼70.1 g of anhydrous ST/100 g of water,25 whereas that of SAT is 46.5 g of anhydrous SA/100 g of water.26 The metastable regions determined in the current study corresponded to the following concentration ranges and degrees of supersaturation (σ = ratio concentration/solubility): STP : X ¼ 0:08 0:19 ð76:9 200:0 g of ST=100 g of water;
σ ¼ 1:1 2:9Þ SAT :
X ¼ 0:10 0:22 ð52:6 125:0 g of SA=100 g of water;
σ ¼ 1:1 2:7Þ
Figure 5. Profile of heat generation from 2.5 mL of sodium acetate or sodium thiosulfate at different supersaturation. Sodium acetate, high (SAH, )) and low (SAL, Δ); sodium thiosulfate, high (STH, 0) and low (STL, O); and SA at σ = 2.15, optimized for dermal application (b) (mean ( SD, n = 3).
associated with a more rapid permeation of lidocaine (∼5 min compared to ∼10 min for a control). After 30 min, the cumulative permeation of lidocaine from the heat generating formulation was over 4-fold higher at 33.7 ( 2.6 μg cm2 compared with the control in which the permeation of lidocaine was 7.8 ( 1.8 μg cm2.
4. DISCUSSION The ability of supercooled salt hydrates to store and generate heat suitable for therapeutic applications was characterized in the current study. The main requirement for medical therapy is a safe and efficacious systems. In the context of dermal hyperthermia, efficacy represents the ability to raise the surface temperature in excess of 32 C (surface temperature of human skin). The salts were selected on the basis of toxicological and cost considerations initially. Further investigation focused on their efficacy:
Spontaneous crystallization occurred for STP above X = 0.19 (i.e., water/ST molar ratio of 4.2:1). Despite the insufficient molar ratio, only the pentahydrate was observed to have crystallized (Figure 2). Due to the incongruent melting of STP, it was impossible to determine whether nuclei of anhydrous ST were present only upon melting, or whether they crystallized concomitantly. The presence of undissolved seeds of anhydrous ST would act as nucleating agents for spontaneous crystallization, which was, indeed, observed above X = 0.19. Spontaneous crystallization upon cooling is common in the case of incongruently melting salt hydrates in the absence of sufficient water and represents a well-known problem with their use as recyclable heat storage systems. The upper metastable limit for SA occurred at a mole fraction of 0.22 (i.e., water/SA molar ratio of 3.5:1), which was sufficient for trihydrate formation. It was clear that for all solutions in the metastable region, effective hyperthermia could easily be produced from PCLs of SA and ST dissolved in water at high temperature and allowed to supercool to room termperature. Following identification of the metastable limits, the factors controlling the heat generation profile were investigated for SAT and STP systems. A theoretical assessment of the heat generation process was performed to identify parameters that could be optimized for therapeutic hyperthermia. The differential equation describing the temperaturetime profile of the PCM (dTPCL/dt) can be written as dR UAðTPCL Tamb Þ Qmax dTPCL dt ¼ i dt Σ mi cp, i 8373
ð2Þ
dx.doi.org/10.1021/jp109518k |J. Phys. Chem. C 2011, 115, 8369–8375
The Journal of Physical Chemistry C where Qmax is the maximum heat that can be generated by exothermic crystallization (i.e., yield enthalpy); dR/dt is the fractional rate of crystallization; U is the complex overall heat transfer coefficient (with the units W m2 K1) acting over a contact area, A; TPCL is the instantaneous temperature of the PCL; Tamb is the temperature surrounding the vial (i.e., 25 C); and mi and Cp,i are the mass and specific heat capacities of the ith component of the PCL, respectively (i.e., solution and solid). The temperature profile is therefore dependent on the crystallization rate, which determines the power of crystallization (dqcrys/dt); the magnitude of total enthalpy, which is recoverable; and the rate of heat dissipation to the environment (loss power: dqdiss/dt). Thus, factors affecting the crystallization rate and the heat loss constant (particularly, the heat capacity of the PCM components, Cp,i) provide strategies for optimization of the temperature profile for therapeutic hyperthermia applications. Following crystallization theory,27 the rate of crystallization is controlled by the supersaturation/supercooling level, the diffusivity of the crystallizing substrate, or both. A high Cp opposes a temperature rise for a given enthalpy release, but is also associated with a lower temperature decrease by dissipation Following the above theoretical analyses, the effects of supersaturation were investigated for SAT and STP phase change systems as a means of controlling the heating profile during crystallization. Two concentration levels (and subsequently, supersaturation, σ) for sodium acetate (X = 0.22, σ = 2.69; X = 0.15, σ = 1.79) and sodium thiosulfate (X = 0.19, σ = 2.85; X = 0.12, σ = 1.78) were selected (see Table 1 for summary of results). The heating profiles are presented in Figure 5. Crystallization of SAT and STP was confirmed by melting point analysis (Figure 2). Thus, the different heating profile (i.e., Tmax and tmax) produced at different supersaturation levels was not associated with the crystallization of alternative solid state forms reported by others,28 which would display different crystallization powers. The largest temperature evolution was observed in the systems with the higher degree of supersaturation (Table 1, Figure 5). However, the kinetic indicators of heating profile are also of importance, which is determined by the rate of crystallization and the specific heat capacity of the respective PCM phases. In the case of nonisothermal crystallization process (e.g., PCL crystallization), the crystallization rate is dependent on the temperature of the reaction and therefore varies during the exothermic crystallization process. The integrated form of the crystallization rate eq 3 takes the form Z t K½Tðt 0 Þ dt 0 ð3Þ gðRÞ ¼ 0
where g(R) is the integrated rate equation and K[T(t0 )] represents the sum of the instantaneous reaction rate constants for times, t0 , earlier than t. Therefore, a gross estimation of the crystallization rate is more useful for comparative purposes between crystallizing systems.29 The syringe method measured a rate for SAT at a high concentration of ∼7 mm s1, which was in agreement with values previously reported.30,31 Slower crystallization rates were measured at the lower supersaturation levels of both SAT and STP, and crystallization rates were lower for STP under all conditions (Table 1). The low crystallization rate results in the slow release of enthalpy to the crystallization medium and, subsequently, a smaller temperature rise (Tmax) according to eq 2. The higher viscosity of STP solutions compared with SAT would reduce
ARTICLE
Table 1. Crystallization Conditionsa and Thermal Performanceb for Sodium Acetate and Sodium Thiosulfate Phase Supercooled Solutions phase change material
SAH
SAL
STH
STL
σ
2.69
1.79
2.85
Y (g)
15.02
10.57
16.97
11.48
Qmax (kJ)
2.17
1.53
3.26
2.21
1.78
rate (mms1)
7.28 ( 0.45 2.61 ( 0.0 0.26 ( 0.21 0.16 ( 0.09
Tmax (C)
55.7 ( 0.3
39.1 ( 0.3 45.5 ( 0.2
38.5 ( 0.2
tmax (s) DUR (s)
15 ( 0 725 ( 35
15 ( 0 335 ( 17
75 ( 0 535 ( 35
140 ( 9 1125 ( 0
a Supersaturation, theoretical yield, and rate. b Maximum generatable heat, Qmax; maximum temperature upon phase change, Tmax; time to maximum temperature, tmax; and time spent above 32 C, DUR.
diffusivity and, hence, the crystallization rate. Furthermore, for salt hydrates, the crystallization rate depends not only on the supersaturation but also on the degree of supercooling (i.e., the difference between storage temperature and melting temperature). Because the melting point of STP (48 C) is lower than SAT (58 C), the degree of supercooling was also lower for STP than SAT. STP and SAT PCLs possessed higher heat capacities (Cp) compared with the dry crystals. With a slow crystallization rate, latent heat is absorbed by the PCL with its high Cp and resists elevation of temperature, but also resists cooling. Consequently, lower temperatures are recorded (Table 1, Figure 5) for STP systems than for SAT, as well as lower Tmax values at at low supersaturation, but DUR increases, even if high temperatures are not achieved (e.g., STP systems, Figure 5). A rapid crystallization rate results in short tmax values (e.g., 15 s for SAT systems). However, because the crystals possess a lower Cp than the PCL, the enthalpy is not retained in the solid state form, and there is lower resistance to heating.32 A high Tmax is achieved, but natural cooling begins to dominate the heat transfer balance, which is more rapid for the solid (lower Cp) than the PCL. Following from the latter observations, an attempt was made to “tune” the composition of the PCM for a meaningful dermal therapeutic application. For the purposes of improving drug permeation across the skin, an elevated temperature of 50 C (Tmax), which should be achieved rapidly (short tmax), is desired due to its safety and potential thermophoretic efficacy.33 An extended duration of elevation (DUR) is also desirable. On this basis, sodium acetate at intermediate supersaturation (σ = 2.15) was selected as the most suitable supercooled salt to use in drug transport studied. A glass vial (2.54 cm2) was chosen because this is a representative surface area for several dermal patches (e.g Transderm Scop 2.5 cm2 and Estradot 25, 2.5 cm2). An effective increase in temperature (Tmax = 51.6 ( 0.3 C) was produced with a DUR suitable for a single use intervention (∼10 min). When applied to a gel formulation of lidocaine, a lower temperature was measured at the membrane surface (due to the presence of the gel phase). Nevertheless, the application of heat generated from the PCM considerably reduced the appearance time of lidocaine permeation through silicone membrane and improved overall drug permeation. From the current investigations, the parameters controlling heat release from phase change materials of therapeutic relevance (i.e., safe with low toxicity) have been identified. The characterization revealed strategies to control the temperature profile for 8374
dx.doi.org/10.1021/jp109518k |J. Phys. Chem. C 2011, 115, 8369–8375
The Journal of Physical Chemistry C dermal therapeutic requirements, including (1) supersaturation to control the mass of salt which crystallizes; (2) supersaturation, supercooling, and viscosity to control the crystallization rate; and (3) relative heat capacities of the supercooled solution and crystalline material. Demonstrating the potential for future application, it was possible to control the crystallization conditions enabling optimization of the heating profile to achieve a therapeutic application.
5. CONCLUSION The key factors affecting the generation of heat from supercooled salt hydrates were investigated in the current study. The study identified a combination of interdependent variables: saturation level, crystallization rate, and heat capacities involved in the exothermic phase change of supercooled salt systems, which will allow the optimization of PCM-based latent heat generation for therapeutic applications. The understanding gained of these variables could lead to the development of therapeutic applications based on supercooled formulations that are capable of producing dermal hyperthermia. ’ ASSOCIATED CONTENT
bS
Supporting Information. Supporting experimental information regarding the selection of suitable salt systems is available. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*Phone: þ44 (0)1707 285904. E-mail:
[email protected]. Present Addresses ^
School of Pharmacy, University of Hertfordshire.
ARTICLE
(12) Brown, M. B.; Martin, G. P.; Jones, S. A.; Akomeah, F. K. Drug Delivery 2006, 13, 175–187. (13) Moritz, A. R.; Henriques, F. C. Am. J. Pathol. 1947, 23, 695–720. (14) Raleigh, G.; Rivard, R.; Fabus, S. Undersea Hyperb. Med. 2005, 32, 445–449. (15) U.S. Food and Drug Administration. EAFUS database. Retrieved on 10 December 2010 from the World Wide Web: http://www. fda.gov/ (16) Cicone, J. S.; Petronis, J. B.; Embert, C. D.; Spector, D. A. Am. J. Kidney Dis. 2004, 43, 1104–1108. (17) Kyriakopoulos, G.; Kontogianni, K. Renal Failure 1990, 12, 213–219. (18) Archer, D. G. J. Phys. Chem. Ref. Data 1993, 22, 1441–1453. (19) TA application note TA265 from TA Instruments (www. tainstruments.com) (20) E1269 Test method for Determining Specific Heat Capacity by Differential Scanning Calorimetry. American Society for Testing and Materials International: West Conshohocken, PA. (21) TA application note TA310 from TA Instruments. (22) Wood, D. G.; Brown, M. B.; Jones, S. A. Int. J. Pharm. 2011, 404, 42–48. (23) Cabeza, L. F.; Svensson, G.; Hiebler, S.; Mehling, H. Appl. Therm. Eng. 2003, 23, 1697–1704. (24) Naumann, R.; Emons, H.-H. J. Therm. Anal. 1989, 35, 1009–1031. (25) Young, S. W.; Burke, W. E. J. Am. Chem. Soc. 1904, 26, 1413–1422. (26) Green, W. F. J. Phys. Chem. 1908, 12, 655–660. (27) Mullin, J. W. Crystallization: Butterworth-Heinemann: Oxford, 2001. (28) Young, S. W.; Burke, W. E. J. Am. Chem. Soc. 1906, 28, 315–347. (29) Murnane, D.; Marriott, C.; Martin, G. P. Int. J. Pharm. 2008, 361, 414–149. (30) Dietz, P. L.; Brukner, J. S.; Hollingsworth, C. A. J. Phys. Chem. 1957, 61, 944–948. (31) Ahmad, J. A. J. Chem. 2002, 14, 223–226. (32) Sandnes, B.; Rekstad, J. Sol. Energy 2006, 80, 616–625. (33) Park, J.-H.; Lee, J.-W.; Kim, Y.-C.; Prausnitz, M. R. Int. J. Pharm. 2008, 359, 94–103.
’ ACKNOWLEDGMENT The authors acknowledge MedPharm Ltd. and the United Kingdom Engineering and Physical Sciences Research Council (EPSRC) for DGW’s CASE studentship award. ’ REFERENCES (1) Farid, M. M.; Khudhair, A. M.; Razack, S. A. K.; Al-Hallaj, S. Energ. Convers. Manage. 2004, 45, 1597–1615. (2) Zalba, B.; Marin, J. M.; Cabeza, L. F.; Mehling, H. Appl. Therm. Eng. 2003, 23, 251–283. (3) Pebler, A. Thermochim. Acta 1975, 13, 109–114. (4) Abhat, A. Sol. Energy 1983, 30, 313–332. (5) Sharma, S. D.; Sagara, K. Int. J. Green Energy 2005, 2, 1–56. (6) Young, S. W.; Mitchell, J. P. J. Am. Chem. Soc. 1904, 26, 1389–1413. (7) Sandnes, B. Am. J. Phys. 2008, 76, 546–550. (8) Hurwitz, M. D. Am. J. Clin. Oncol. 2010, 33, 96–100. (9) Yoshida, M.; Watanabe, Y.; Sato, M.; Maehara, T.; Aono, H.; Naohara, T.; Hirazawa, H.; Horiuchi, A.; Yukumi, S.; Sato, K.; Nakagawa, H.; Yamamoto, Y.; Sugishita, H.; Kawachi, K. Int. J. Cancer 2010, 126, 1955–1965. (10) Akomeah, F.; Nazir, T.; Martin, G. P.; Brown, M. B. Eur. J. Pharm. Sci. 2004, 21, 337–345. (11) Zars Website. Retrieved on 31 March 2009 from the World Wide Web: http://www.zars.com/ 8375
dx.doi.org/10.1021/jp109518k |J. Phys. Chem. C 2011, 115, 8369–8375
