Abstract
Plastic materials are widely used in medical items such as solution containers, infusion sets, transfer tubing, devices, processing equipment and systems, filters, and the like. Components in medical items can leach out of such items when they are contacted by a therapeutic product or product-related solution. Stearic acid and stearate salts are commonly present in medical and food packaging, either as plastic additives, processing aids, or contaminants, and their leaching from plastics is well documented. With a pKa in the range of 5.1 to 5.6 and limited aqueous solubility (log Po/w greater than 8), the leaching of stearic acid (and its related metal salts) into pharmaceutical products is expected to be strongly dependent on the product's pH and polarity. In order to establish and understand the leaching behavior of stearate-containing materials, three compounds (stearic acid, calcium stearate, and zinc stearate) and four polymeric materials containing these compounds were contacted with aqueous buffers in the pH range of 2.5 to 11. The leached levels of calcium, zinc, stearate, palmitate, and total organic carbon (TOC) were measured in the resulting solutions and are reported. For materials containing only stearic acid or salts themselves, the extraction of these entities is pH-dependent. At low pH, the cation counter-ions of the stearate salts are extracted from the plastic materials by a process that can loosely be termed ion exchange. At intermediate pH, little or no extraction of the stearates occurs. At high pH, the stearates are extracted from the materials to a very limited extent due to the solubility of the acid and/or salts in the extraction medium.
1. Introduction
Plastic materials are widely used in medical items such as solution containers, infusion sets, transfer tubing, devices, processing equipment, and systems, filters, and the like. In order to exhibit the performance characteristics required in medical applications, the plastics are formulated from base polymers and include numerous functional additives. Such additives, their related substances, impurities in the base polymer, processing aids related to polymer/item production, and environmental contaminants can leach out of the medical items when they are contacted by a therapeutic product or product-related solution. The specific leached substances, their accumulation levels in the product or solution, and the manner in which the product or solution is used combine to dictate whether this leaching affects product/solution safety or efficacy.
Stearic acid and stearate salts are commonly present in the plastics used in medical and food applications (1–4), either as plastic additives, processing aids, or contaminants, and their leaching from plastics is well documented (5–10). With a pKa in the range of 5.1 to 5.6 (11–13) and limited aqueous solubility (log Po/w greater than 8) (14), the leaching of stearic acid (and its related metal salts) into pharmaceutical products is expected to be strongly dependent on the product's pH and polarity. For example, log D for stearic acid varies from approximately 8.2 to 4.5 over the pH range of 1 to 10. While the impact of extracting medium properties on leaching of fatty acid anions from an irradiated ethylene-vinyl acetate (EVA) material has been reported (10), the data presented did not include a consideration of the acid anion's cationic counter-ion and considered only a single EVA material whose fatty acid source was unknown.
In order to establish and understand the leaching behavior of stearate-containing materials, three compounds (stearic acid, calcium stearate, and zinc stearate) and four polymeric materials containing these compounds were contacted with aqueous buffers in the pH range of 2.5 to 11. To investigate the accumulation of stearate-related entities in solutions in contact with plastic materials containing stearate salts, the levels of calcium, zinc, stearate, palmitate, and total organic carbon (TOC) were measured in the resulting solutions and are reported.
2. Experimental Design
2.1. Materials
The salts used in the dissolution study were all obtained from commercial vendors as follows: stearic acid (CAS RN 57-11-4), Aldrich (Milwaukee, WI), 98%+ purity; zinc stearate, Sigma-Aldrich (St. Louis, MO), technical grade, contains ∼65% stearate salt (557-05-01), ∼25% palmitate salt (4991-47-3); and calcium stearate, Sigma-Aldrich, 9.0–10.5% as CaO, consisting of a mixture of calcium stearate (1592-23-0) and calcium palmitate (542-42-7).
The plastics used in the extraction study were obtained from commercial vendors and were as follows: polypropylene resin (PP), reported to contain 300 ppm (weight basis) calcium stearate; high-density polyethylene (HDPE) film, target composition of 1800 ppm calcium stearate; plasticized polyvinyl chloride (PVC) resin, containing 0.2 phr (parts-per-hundred) of a mixed calcium/zinc stearate salt; and elastomer (synthetic polyisoprene), containing zinc oxide and stearic acid in unspecified proportions.
Reagents, chemicals, and solvents used in the preparation of the extraction/dissolution buffers and preparation of analytical solutions were either American Chemical Society (ACS) or reagent grade, obtained from appropriate commercial vendors.
2.2. Preparation of Dissolution/Extraction Buffers
Buffers containing ≈0.05 M sodium phosphate monobasic monohydrate were prepared at pH values of 2.5, 3.0, 3.5, 4.0, and 4.5 by addition of phosphoric acid to achieve the desired pH. Buffers containing 0.05 M KH2PO4 were prepared at pH values of 5.0, 5.5, 6.0, 6.5, 7.0, and 7.5 by appropriate pH adjustment with either sodium hydroxide or hydrochloric acid. Buffers containing 0.025 M borax (sodium tetraborate decihydrate) were prepared at pH values of 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, and 11.0 by addition of either sodium hydroxide or hydrochloric acid. The pH of the buffers was confirmed after preparation.
2.3. Dissolution Study
Replicate test units were prepared for each salt solution pH couple by suspending ≈2.5 to 5.0 mg/mL of solid in the buffers. The test units were stored at ambient temperature with constant gentle agitation for ≈13 days. After this point, the agitation was stopped and the remaining solid was allowed to aggregate. After aggregation was complete (visual confirmation of separation of solid and liquid phases), portions of the solution phase were carefully obtained and analyzed. It is noted that the solutions of zinc stearate material at pH 10 and higher had a hazy appearance even after the bulk of the remaining solid had aggregated. However, the haze dissipated and a clear sample could be obtained after dilution and additional room temperature storage. Dissolution blanks, containing only portions of the dissolution solutions, were also prepared and analyzed.
2.4. Extraction Study
Portions of the test materials were contacted with the extraction media in Pyrex® extraction vessels. The material weight-to-extraction solution volume varied from material to material based on two constraints, ability to ensure adequate contact between the material and extraction solution, and the lack of visible particulate formation. The PP and PVC resins were extracted at a material weight-to-solution volume ratio of ≈0.3 g/mL. As the HDPE film was a less “massive” material than the resins, it was extracted as a less “concentrated” mixture (≈0.09 g/mL) so that the entire amount of material was contacted by extraction solution.
The stoichiometry of the elastomer extracts varied greatly as a function of pH because at the highest pH a precipitate was formed if the material weight-to-solution volume ratio was too high. At pH values less than 8.0, the extraction stoichiometry was ≈0.007 g/mL. For the high pH extractions, the stoichiometry decreased from ≈0.007 g/mL at pH 8.0 to ≈0.003 g/mL at pH 11.
The test units were stored at ≈70 °C for a period of ≈3 days. After the stored test units had equilibrated to ambient temperature, portions of the solution phase, which were clear and visually free from particulate, were carefully obtained and analyzed (after appropriate dilution as necessary). Extraction blanks, containing only portions of the extracting solutions, were also prepared and analyzed.
2.5. Analytical Methods
The stearate and palmitate analyses were performed via direct injection liquid chromatography with mass spectrometric detection (LC/MS), via a methodology similar to that reported previously (10). These analyses were accomplished with an Agilent 1100 high-performance liquid chromatography (HPLC) system (pumping system, autosampler, column chamber, ChemStation data system) coupled with an Agilent 1100 mass spectrometry detector (MSD). The samples were analyzed by direct injection, with no sample preparation other than dilution as appropriate. The calcium and zinc determinations were performed by inductively coupled plasma atomic emission spectroscopy (ICP-AES) with a Varian (Walnut Creek, CA) Vista-Pro CCD Simultaneous ICP-OES, operated with a V-groove nebulizer and a glass cyclonic double-pass spray chamber. While most of the samples were analyzed by ICP-AES with no sample preparation, the high-pH samples were digested in mineral acid to eliminate matrix-related interferences.
The TOC analyses were performed with an OI Analytical (College Station, TX) model 1010 TOC Analyzer operated as follows: TOC Mode, 1 mL sample, oxidant = 100 g/L sodium persulfate (1000 μL), acid = 5% phosphoric acid (200 μL), extended reaction time of 20 min, reaction temperature = 97 °C.
3. Results and Discussion
3.1. Dissolution of Stearic Acid Salts
The dissolution data for calcium stearate are shown in Table I. The concentration of stearate ion in solution is low and is not materially affected by solution pH over the entire range studied, although there is some evidence that at a pH above 6.5 the solubility of calcium stearate increases somewhat and the stearate level in solution increases. Alternatively, the concentration of calcium ion in solution is strongly affected by solution pH and increases significantly at pH values lower than 6.0. Even at the higher pH values, the concentration of calcium ion in solution greatly exceeds the stoichiometric equivalent of calcium stearate. Specifically, calcium stearate, Ca(stearate)2, has a stearate-to-Ca weight ratio of 2(283.5):40.08 or ≈14. Thus, if both Ca and stearate were derived from calcium stearate dissolution, the Ca concentration that corresponds to 0.3 mg/L stearate (which is approximately the average amount in the test solutions) would be 0.3:14 or 0.02 mg/L. Even at its lowest levels, Ca is present in the test solutions at levels over 100 times this value. Thus it is clear that a majority of the Ca in solution is not associated with calcium stearate dissolution. Rather, the Ca stearate solid is being “titrated” by the acid; specifically, the hydrogen ion is displacing the Ca ion in the solid, resulting in its conversion from Ca stearate to H stearate (stearic acid). It is noteworthy that this increase in Ca concentration in solution corresponds to a significant increase in the measured solution pH versus its initial preparation value. However, the decrease in hydrogen ion concentration reflected in the pH change is not stoichiometrically equivalent to the increase in calcium ion concentration. For example, at pH 2.5, the pH changed from an initial value of 2.5 to a value of approximately 2.9, reflecting the loss of approximately 0.0018 moles/L of hydrogen ion. Alternatively, the average concentration of dissolved calcium ion in the pH 2.5 solution is approximately 139 mg/L, corresponding to 0.0035 moles/L. Thus, more calcium is being dissolved than hydrogen ion is being neutralized. The excess calcium is accounted for via the formation of Ca-phosphate ion pairs, as phosphate is the buffer system counter-ion.
Dissolution Characteristics, Calcium Stearate
Considering the pH data further, it is noted that when the starting pH is low (pH 2.5), the pH increases toward a value of approximately 6.0 but does not achieve this value. The reason that the pH of the pH 2.5 solution does not increase to a value higher than 3.0 is because the buffering capacity of the test system has been exceeded. The reason the buffering capacity is exceeded is that all the available calcium has been exchanged. This is illustrated as follows. The pH 2.5 sample contained 0.15 g of calcium stearate per 60 mL of solution or 2.51 g/L. The calcium equivalent to 2.51 g/L calcium stearate is 164 mg/L, which is the approximate Ca concentration in the pH 2.5 solution (166 mg/L, from Table I). For the pH 2.5 sample, then, all the available Ca has been exchanged and used up before significant Ca-phosphate ion pairing occurs. Thus the pH starts to increase but cannot reach a value higher than 3.0. For the samples that start at a pH of 3.0 or higher, however, there is sufficient Ca in the Ca stearate so that all the acid is neutralized and significant Ca phosphate ion pairing occurs. The formation of the ion pairs, along with the excess Ca stearate, produces a mixed-phase system with a considerable buffering capacity in the pH range of 5.0 to 6.0. Thus, the final pH of the solutions that had an initial pH in the range of 3.0 to 5.0 approaches 5.7 to 5.9.
The dissolution data for zinc (Zn) stearate are shown in Table II. The behavior of Zn stearate essentially mirrors that of Ca stearate. However, given Zn's higher atomic weight versus Ca, the behavior of the pH of those solutions with an initial pH of less than 6.0 is exaggerated, Zn stearate versus Ca stearate. Because an equal weight of Zn stearate (versus Ca stearate) will contain fewer moles of Zn, the pH lag for the Zn stearate is more pronounced than for the Ca stearate (as there is a smaller Zn pool in Zn stearate than Ca in an equal weight of Ca stearate). Additionally, there may be a small difference in the formation constant, Zn phosphate ion pairs versus Ca phosphate ion pairs. The increase in stearate solubility at the highest solution pH values is more pronounced for the Zn stearate than for the Ca stearate.
Dissolution Characteristics, Zinc Stearate
The stearic acid dissolution data are shown in Table III. Small amounts of dissolved Ca and Zn indicate that the stearic acid salt contains some small levels of Ca- and Zn-containing impurities. As was the case with the Ca and Zn salts, the stearate solubility is low at all pH values but does discernibly increase above a pH of 6.0, roughly corresponding to the pKa of stearic acid (5.1–5.7) (11–13).
Dissolution Characteristics, Stearic Acid
Plots reflecting the concentration of the various entities of interest as a function of solution pH are shown in Figure 1.
Dissolved concentrations of the various components of the solid materials investigated in this study. The calcium data reflects the concentration of this analyte in the solutions equilibrated with calcium stearate. The zinc and stearate data reflect the concentrations of these analytes in the solutions equilibrated with zinc stearate. At low pH, calcium and zinc are released from their respective salts via an ion exchange process. Actual dissolution of the stearate materials occurs in limited amounts only at high pH.
3.2. Extraction of Stearates from Plastic Materials
The PP resin and HDPE film are similar materials in that they are polyolefin structures that contain a known, small amount of calcium stearate. The leaching of calcium stearate from these two materials is similar in nature but differs in magnitude due to the differing amounts of extracted film and their differing levels of the calcium stearate (Table IV). For both materials, Ca leaching increases as the pH of the extraction solution decreases, although the levels of leached Ca are not large at any pH. Conversely, the level of extracted stearate increases with increased solution pH, with the rate of increase escalating considerably above a pH of 8.5. At both high and low pH it is clear that the entity that is being leached from the material is not the parent compound (e.g., the stearate salt) but rather the associated ion (e.g., stearate or calcium ion). Thus, for example, the amount of Ca leached at high pH is not stoichiometrically equal to the amount of stearate leached, and thus stearate is leached as the ion and not the Ca stearate salt. Similarly, at low pH the amount of stearate leached is not stoichiometrically equal to the amount of Ca that is leached, and thus the Ca is leached as the ion and not the Ca stearate salt.
Composition of Extracts of the Polypropylene Resin
In general, the extraction trends for the plastic materials are the same as the dissolution trends for the Ca stearate salt with two major exceptions. First, the level of Ca extracted from the plastics at low pH is much less than the level of Ca extracted from the Ca stearate salt (compare Table IV and Table I). Second, the level of stearate extracted from the plastics at high pH is much greater than the level of stearate extracted from the Ca stearate salt. Some of these differences can be accounted for by the differing nature of the salt and plastic extractions. While the salt dissolution units typically reflected a very concentrated test sample (2.5–5.0 mg/mL of extracted salt), the plastic extraction units typically involved much less salt (e.g., the amount of Ca stearate in the extracted PP resin was approximately 0.09 mg/mL). This difference in amount of solubilized material, salt versus plastic, is “in trend” for the Ca data (more Ca leached from the salt than from the plastic because the salt had more available Ca stearate) but is out of trend with respect to stearate. Thus, more stearate is leached from the plastic than would be solubilized from its corresponding stearate-containing salt. It is estimated that at the highest level, stearate leached from the PP material (at pH 10.5 and 11) is approximately 8.2% of this material's total available stearate.
The behavior of the PVC resin, which contains a mixed Ca/Zn stearate salt as an additive, is analogous to the behavior of the polyolefin materials (Table V). Apparently, the mixed salt used in the PVC formulation is dominantly the Zn salt, as the levels of extracted Zn are much higher than the levels of extracted Ca. In terms of the extracted cations, there is a discernible change in extracted metal levels between pH 7.5 and 8.0. This transition occurs with the change in the buffering system from borate to phosphate and thus is not related to solution pH. In fact, within a given buffer system, the levels of extracted cations are roughly constant over the pH range studied.
Composition of Extracts of the Polyethylene Film
Stearate leaching increases considerably above a pH of 8.5 to 9.0, similar to the polyolefin materials.
In general, most of the extracts of the PVC material were visually free of particulate matter. However, when the very high pH extractions units were stored for longer periods of time (for example, while awaiting analysis), clouding of the solutions was observed. Portions of these cloudy extracts were filtered, and the collected particulate was examined to determine its identity (X ray fluorescence spectroscopy and infrared spectroscopy). It was concluded that the cloudy particulate was predominately sodium stearate, with small amounts of a secondary plasticized PVC additive. The high-pH samples contain considerable amounts of sodium (the borate buffer was a sodium salt); this suggests that the longer storage of these samples caused enough stearate to be leached that the solubility product of sodium stearate was exceeded.
The elastomer studied is different than the other materials in one important respect, as it contains independent sources of stearate (stearic acid) and a cation (zinc oxide). As shown in Table VII, this material behaves in a manner similar to the other studied materials in two major ways. First, significantly more metal is leached into the phosphate buffer (lower pH) compared to the borate buffer (higher pH). Secondly, the extracted stearate levels increase considerably as the pH of the extraction solution increases past 8.5 to 9.0. Despite these similarities to the other examined materials, the elastomer's behavior at high pH is dramatically different than that of the other materials in one important aspect. While the high pH extracts of the other materials were visually clear from particulate at relatively high material weight-to-solution volume loadings, the high pH elastomer extracts at similar loadings contained readily discernible amounts of particulate. In fact, the material loading in the high-pH elastomer extracts had to be reduced by a factor of 100 (versus the loading for the other materials) for the extract to remain clear of particulate. Portions of cloudy pH 11 extracts of the elastomer were filtered, and the collected particulate was examined to determine its identity. It was concluded that the particulate was a mixture of zinc stearate and a mixed Zn/stearate salt (i.e., a salt containing zinc, stearate, and undetermined additional component[s]). Clearly there is sufficient extracted zinc that in this case that the solubility product for zinc stearate is exceeded, resulting in its precipitation. Specifically, stearate from one source (stearic acid) and a precipitating cation from another source (metal oxide) are extracted from elastomer and meet in the extracting solution. Because the metal stearates are highly insoluble, the cation and stearate ion accumulate to levels that exceed the solubility product of the cation-stearate salt, resulting in the precipitation of that salt.
Figures 2 and 3, which illustrate the solution concentrations of the entities leached from the PVC resin and the elastomer, document the very different behaviors of these two materials.
Levels of substances extracted from the PVC resin that contained amMixed Ca/Zn stearate salt. The leaching characteristics of the PVC resin is similar to the interaction characteristics of the individual steatate salts in that small quantities of the cations are leached from the resin at low pH and larger quantities of the stearic acid (and its more soluble impurity palmitic acid) are leached at higher pH.
Levels of substances extracted from the elastomer that contained stearic acid and zinc oxide. The fact that this material contained independent sources of precipitating ions (cations and stearate) resulted in a more complex leaching profile than those profiles which were obtained for the other materials studied. The amounts of extracted zinc and stearate were sufficiently high at high pH that a zinc stearate precipitate was observed in the high pH extracts.
The formation of precipitates in material extracts or pharmaceutical solutions contacting a plastic material is well documented in the literature. For example, Markovic documents a case in which barium leached from glass vials precipitated as the sulfate salt due to the presence of a sodium sulfate excipient (15). Boddapati and associates also report barium sulfate precipitation arising from barium ions leached from borosilicate glass with sulfate ions that either reflect the drug counter-ion or are derived by oxidation of a bisulfite antioxidant (16). Castner reports the formation of zinc phosphate precipitates in diluent vials, where the zinc is a rubber stopper leachable and the phosphate is the diluent buffer (17).
The extracted TOC (TOC in extract minus TOC in extraction blank) data are contained in Tables IV through VII. While the absolute levels of extracted TOC were different, material-to-material, in general the extracted TOC increased with increasing extraction solution pH, mirroring the trend in the levels of extracted stearate and palmitate. It is likely, however, that the extracted TOC reflects the extraction of organic compounds other than stearate and palmitate, as the levels of the extracted TOC are typically higher than the corresponding TOC associated with these two fatty acids alone.
Composition of Extracts of the PVC Resin
Composition of Extracts of the Elastomer
4. Conclusion
The extraction of stearate and its cationic counter-ions from plastic materials containing stearic acid or stearate salts has been investigated as a function of the pH of the extracting solutions. Dissolution studies were performed on stearic acid and its calcium and zinc salts in order to facilitate an understanding of the extraction behavior of these compounds. For materials containing only stearic acid or salts themselves, the extraction of these entities is pH-dependent. At low pH, the cation counter-ions of the stearate salts are extracted from the plastic materials by a process that can loosely be termed ion exchange. At intermediate pH, little or no extraction of the stearates occurs. At high pH, the stearates are extracted from the materials to a very limited extent due to the solubility of the acid and/or salts in the extraction medium.
The extraction properties of materials that contain both a stearic acid salt and a material possessing a potentially precipitating cation are such that the formation of particulate matter during the extraction is possible. This phenomenon was demonstrated in high-pH extracts of an elastomeric material that contained both zinc oxide and stearic acid. Under such high-pH conditions, zinc and stearate are independently extracted from their source materials at levels that exceed the solubility product of the zinc stearate salt, resulting in its precipitation.
Ackowledgments
The expert analytical support provided by members of Baxter's Physical and Chemical Sciences Department, including Camiellia Shumpert, Salma Sadain, Thang Tran, Tammy Mortensen, Kirk Ashline, Lucita Aralar, Molly Chacko, Eric Edgcomb, Nazeer Khan, and James Troedel, is acknowledged and greatly appreciated.
- © PDA, Inc. 2010
