Research Article
Interactions of Per
fluorohexyloctane With Polyethylene and
Polypropylene Pharmaceutical Packaging Materials
Yana Znamenskaya Falk
a,b, Anna Runnsj€o
a,b, Anthony Pettigrew
c, Dieter Scherer
d,
Johan Engblom
a,b, Vitaly Kocherbitov
a,b,*aBiomedical Science, Faculty of Health and Society, Malm€o University, SE-205 06 Malm€o, Sweden bBiofilms e Research Center for Biointerfaces, Malm€o University, SE-205 06 Malm€o, Sweden cAnthony Pettigrew Associates Ltd, Liverpool, UK
dApisPharma AG, CH-4242 Laufen, Switzerland
a r t i c l e i n f o
Article history: Received 16 February 2020 Revised 19 March 2020 Accepted 25 March 2020 Keywords: Semifluorinated alkanes Leachables Extractables Polypropylene Polyethylene Thermal analysis Phase diagrama b s t r a c t
Semifluorinated alkanes (SFAs) are aprotic solvents, which may be used as drug solvents for topical ocular applications, for instance, in dry eye syndrome. Their physical properties suggest that they might be prone to interaction with plastic materials, such as, polyethylene (PE) and polypropylene (PP), which are commonly used as packaging materials for pharmaceutical products. In this study, we investigate interactions of PE and PP with a liquid SFA perfluorohexyloctane (PFHO) using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and cross-polarized light microscopy. Binary phase diagrams of PFHOePE and PFHOePP systems demonstrating interactions of PFHO with the polymeric materials were constructed based on DSC data. According to this data, PFHO tends to lower the melting temperatures of PE and PP. The equilibrium values of solubilities of the polymers in PFHO and PFHO in the polymers were obtained by extrapolation of melting enthalpy data. Absorption of PFHO by PE and PP materials at ambient conditions after four weeks of equilibration was also studied by TGA. From the presented results, it may be concluded that thorough studies of interactions of PE or PP with SFAs are required when these materials are used as packaging components in SFA-based formulations. © 2020 The Authors. Published by Elsevier Inc. on behalf of the American Pharmacists Association®. This
is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
Introduction
Semifluorinated alkanes (SFAs), sometimes called primitive sur-factants,1are diblock molecules, containing two chemically different moieties, a perfluorinated chain and a hydrogenated fragment, which are bound covalently. They can generally be described by formula Fe(CF2)ne(CH2)meH, abbreviated as FnHm.2,3 SFAs are
inert, non-toxicfluids, capable of dissolving lipophilic drugs.1Such properties of SFAs make them ideal candidates as drug solvents for topical ocular applications, for instance, in dry eye syndrome.4-6
Packaging of pharmaceutical products is aimed at ensuring that the quality of the formulation is maintained and protected against adverse external influences during shelf life. Compatibility of the packaging system and the formulation has to be shown proving
that no serious interaction occurs that may lead to altering efficacy and stability of the product or present a risk of toxicity.7 Further-more, the choice of packaging materials should also be made in a way that the product does not have an unfavourable effect on the packaging, changing its protective properties.
Possible interactions between a packaging component and a formulation can be divided into two different types: migration of chemical components of the packaging material into the formula-tion (leaching) and sorpformula-tion of the formulaformula-tion components by the packaging material.8
When describing thefirst type of interaction, two closely related terms are often used: extractables and leachables. Extractables are substances that can be extracted from packaging materials using solvents and conditions designed to be more aggressive than the conditions of use, whereas leachables are substances that are pre-sent in the drug product because of its interaction with a packaging material during its intended use.9 Since extractables can be considered as potential leachables, they characterise the packaging * Corresponding author. Faculty of Health and Society, Malm€o University, SE-205
06 Malm€o, Sweden.
E-mail address:Vitaly.Kocherbitov@mau.se(V. Kocherbitov).
Contents lists available atScienceDirect
Journal of Pharmaceutical Sciences
j o u r n a l h o me p a g e :w w w . j p h a r m s c i . o rg
https://doi.org/10.1016/j.xphs.2020.03.026
0022-3549/© 2020 The Authors. Published by Elsevier Inc. on behalf of the American Pharmacists Association®. This is an open access article under the CC BY-NC-ND license
material rather than the drug product, while actual leachables are identified and quantified by analysing the drug product.10
While discussions on leachables and extractables focus on the toxicity of these impurities, sorption of drug formulation compounds has an influence on the dosage of the active pharmaceutical ingre-dient.11While sorption of active ingredient may result in reduced drug delivery to the patient, sorption of a solvent (especially followed by permeation to the environment) may lead to uncontrolled in-crease of the active ingredient concentration and/or its precipitation. Polyethylene (PE) and polypropylene (PP) plastic bottles are commonly used for the packaging of ophthalmic products. In this study we investigate interactions of PE and PP with a liquid SFA using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The applications of thermal analysis in the pharma-ceutical industry are well established and growing: the melting behaviour and the glass transition determination of polymers used for packaging materials, polymorphism characterisation of phar-maceutical solids or detection of solvent entrapped in crystals or packaging materials12-14are typical examples. Here, we propose and test a thermal analysis-based protocol for the investigation of possible interactions between formulation and plastic packaging, which can be used in modelling potential product-packaging-interactions during early stage pharmaceutical container closure system development.
Materials and Methods Materials
Perfluorohexyloctane (PFHO, IUPAC name 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane, CAS number 133331-77-8, LOT: 065_Dest_F6), 5 mL natural polyethylene bottle, gamma sterilized (Gerresheimer LOT: 2980513A00) and 5 mL natural polypropylene bottle, ethylene oxide sterilized (Gerresheimer, LOT: 2050713000) were provided by Novaliq GmbH (Heidelberg, Germany).
Differential Scanning Calorimetry (DSC)
The thermal phase behavior of the PFHOePE and PFHOePP systems was studied by DSC (DSC 1, Mettler Toledo, Greifensee, Switzerland). Prepared samples of PE or PP pieces mixed with PFHO in aluminum DSC pans werefirst scanned from 70 to 190C, kept
isothermally for 10 min at 190C to erase thermal history of plastic materials and allow components to mix completely, then cooled again down to70C and immediately heated to 190C. Heating rates of 1 or 10C/min were used. Calibration for heatflow and temperature was performed using indium (Tm ¼ 156.6 C;
D
H¼ 28.45 J/g). Samples were inserted into 40m
L aluminium pans (40m
L, Mettler Toledo) and hermetically sealed. An empty sealed pan was used as a reference during all experiments. The furnace was purged with dry nitrogen gas at aflow rate of 80 mL/min. The following concentrations of PE were used: 0, 2.35, 5.98, 12.27, 20.03, 30.31, 40.24, 45.89, 62.06, 77.96, 86.94, 95.16 and 100 wt%. The following concentrations of PP were used: 0, 5.37, 12.82, 16.72, 26.34, 33.47, 44.63, 53.53, 63.62, 70.01, 79.20, 86.86 and 100 wt%.Thermogravimetric Analysis (TGA)
TGA (Q500 TGA, TA instruments) was used for the quantification of the amount of PFHO penetrating into the packaging materials. The weight loss of the studied samples as a function of time or temperature was determined. Samples were placed in platinum pans and heated from 25C up to 600C at a heating rate of 10C/ min. TGA data were analyzed using TA Universal Analysis 2000 software (TA Instruments).
Different methods of sample preparation for solvent determi-nation in PE and PP packaging materials were used. They are briefly summarised inTable 1. In method 1, PE or PP pieces were incubated in an excess of PFHO for 1 and 4 weeks at 25, 40 and 70C. Addi-tionally, PP samples were incubated in PFHO for 36e40 weeks at 25, 40 and 70C. Immediately after removal of excess PFHO, the polymer pieces were characterized in TGA.
In method 2, PE and PP pieces and PFHO were mixed in a vial, heated in the oven up to 190C, cooled down to 25, 40 and 70C and then equilibrated for several days at the corresponding tem-peratures. Afterwards, the solid part from the mixture was taken and examined in TGA. In method 3, PE and PP pieces were heated up to 180e190C and cooled down to room temperature. Then 500
m
L PFHO was added to the polymers, and the samples were stored at 25, 40 and 70C for a week. Afterwards, PE and PP pieces were analyzed in TGA.For analysis of the solubility of PE and PP in PFHO, the polymer pieces were inserted into a vial, and 5 mL of PFHO was added. Samples were heated up to 180e190C, then cooled down and stored at temperatures 25, 40 and 70C for 4 days. Afterwards the liquid part of the samples was analyzed in TGA.
Cross-Polarized Light Microscopy
Pieces of untreated PP and PP pre-treated with PFHO were examined using a polarized light microscope equipped with a digital camera DS-2Mv (Nikon, Optiphot, Japan) and a heating table Analysa LTS350 (Linkam, UK). First, PP pieces and PFHO were mixed in a vial, heated in an oven up to 190C and then cooled down at room temperature. Afterwards, the solid part from the mixture was taken and placed onto a microscope slide, heated to 190C in the oven until melted and immediately covered. The same sample preparation was performed for native PP pieces without mixing with PFHO. Microscope slides were examined during heating from 25C to 180C at a heating rate of 10C/min and images were taken atfixed intervals.
Wide Angle Xeray Scattering (WAXD)
For WAXD measurements on polyethylene (PE) and poly-propylene (PP), a compact Kratky camera with line collimation from HECUS (Graz, Austria) was used. CuK
a
-radiation with wave-lengthl
¼ 1.54 Å was used as X-ray source. The samples of PE and PP pieces were mounted in sealed holders between two polymer windows and measured in vacuum. Wide angle (q¼ 1.2e2.0 Å1)spectra for native PE and PP were recorded. All measurements were done for 30 min at 25C.
Table 1
Methods of Sample Preparation for TGA Experiments.
Step 1 Step 2 Step 3 Step 4
Method 1 e e Mixing Equilibration at target temperature
Method 2 Mixing Heating up to 190C and cooling e Equilibration at target temperature
Method 3 e Heating the polymer up to 190C and cooling Mixing Equilibration at target temperature Y.Z. Falk et al. / Journal of Pharmaceutical Sciences xxx (2020) 1-9
Results and Discussion DSC Results
To investigate the basic interactions of PFHO and plastic phar-maceutical packaging materials, we mapped phase diagrams of polyethylene (PE)ePFHO and polypropylene (PP)ePFHO. For that purpose, thermal characterization of PEePFHO and PPePFHO sys-tems at different concentrations was performed by DSC. First, thermal analyses of each component of the studied systems were performed.
Fig. 1showsfirst and second DSC scans of PFHO, PE and PP, where thermal properties of the studied samples are monitored versus temperature. Pure PFHO displays two endothermic transitions, that is a solid-solid transition with onset at43.5C and a melting transition
with onset at6.3C, and enthalpies of 1.2 J/g and 40.5 J/g
corre-sponding to 0.5 kJ/mol and 17.5 kJ/mol respectively (Fig. 1a). Both transition temperatures are in agreement with previous studies on PFHO.15The solid-solid transition is dependent on the chain length of the hydrocarbon part in the molecule, while the melting transition is dominated by the disordering of thefluorocarbon part.16,17The nature of solid-solid transition originates from the liquid crystalline e liquid crystalline phase transition,1,18caused by a change in the molecular packing for the molecular rearrangement.16
First and second DSC scans of PE (Fig. 1b) and PP (Fig. 1c) show that the melting transition temperatures of plastic materials are at 112C and 148C, respectively. The melting transition tempera-tures are in agreement with the data obtained in previous studies
on PE and PP.19-21A comparison of PE and PP melting peaks on the first DSC scans clearly shows that the melting peak of PP is less sharp compared to the PE melting peak. This observation can be explained by the structural difference between PE and PP polymer materials used in this study. First, the visual difference between PE and PP bottles is clearly seen in Figure S1 (SI). It demonstrates higher transparency for PP bottles, while translucency is shown for PE bottles. The degree of transparency of a polymer layer depends on its structure, where amorphous material appears transparent, while crystalline e translucent.22To confirm it, WAXD measure-ments of PE and PP plastic packaging materials were performed and presented inFigure S2 (SI).Figure S2ashows WAXD spectra of PE, where two clear peaks are displayed at q values of 1.5 Å1 and 1.66 Å1, corresponding to d spacing of 4.18 Å and 3.78 Å, respec-tively. Such values correspond to the (110) and (200) reflections of the orthorhombic crystalline structure and are in good agreement with literature.23However, WAXD spectra of PP (Fig. S2b) show a less pronounced peak at q value of 1.52 Å1(d¼ 4.15 Å). Peaks at similar positions are observed in X-ray studies of isotactic and syndiotactic forms of polypropylene and their blends.24,25 The broadness of this peak characterizes the PP packaging material as less crystalline compared to PE. This agrees with the fact that the enthalpy of melting for PE is almost twice as high as the enthalpy of melting for PP (the material with higher crystallinity requires higher energy to melt). Obtained results clearly show that PE plastic material has a higher degree of crystallinity as compared to PP material.
DSC data also demonstrate a difference betweenfirst and sec-ond scans for each polymer material (Fig. 1bandc). In particular, the step seen on the DSC curves in thefirst scan between 40C and
70C, is absent in the second scan for both plastic packaging ma-terials. This observation can be explained by the fact that the sample had already been heated in thefirst DSC scan, where its thermal history had been erased. This transition has previously been assigned to a relaxation of a rigid amorphous fraction in PE system.26This fraction may consist of long branched chains located at the surface of crystals, which could not enter into the crystal unit cell and not move as free as the chains in the amorphous region. Thermal treatment of the PE sample has also been shown to affect this transition.26 In conclusion, obtained data of PE and PP demonstrate a difference in their structural properties, which might result in a different phase behavior for PFHOePE and PFHOePP systems.
Fig. 2demonstrates DSC scans at a heating rate of 10C/min for PFHOePE and PFHOePP systems of a wide concentration range. DSC scans for both systems demonstrate a composition de-pendency in the melting endotherms. First, an increase in PFHO content results in an increase of PFHO solid-solid transition and melting peaks for both systems (Fig. 2). Secondly, an increase in PFHO content leads to a decrease of PE and PP melting peaks in the studied systems (Fig. 2a and 2b, respectively). Moreover, it is
clearly seen that PFHO influences the melting temperatures of PE and PP, lowering the endset of melting. For higher resolution of the PFHO effect on plastic packaging materials, DSC scans were also performed at lower heating rate, 1C/min (Fig. S3). The re-sults demonstrate that addition of PFHO has a plasticization effect on PE and PP plastic packaging materials only up to certain con-centrations. In particular, PFHO addition up to 22 wt% tends to lower the endset temperature of PE melting, while higher con-centrations of PFHO do not seem to lower this temperature further. In the case of PFHOePP system, addition of SFA follows similar scenario up to 46 wt%.
Based on the DSC data, obtained for the PFHOePE and PFHOePP systems, the values of enthalpies of melting can be calculated. Dependences of enthalpy of melting on polymer contents in PFHOePE and PFHOePP systems are shown in Fig. 3a and 3b, respectively. Fig. 3ashows the enthalpies of melting of PE (red symbols) and PFHO (blue symbols). It shows a linear decrease of the enthalpy of PFHO melting with increasing PE content in the system. The observed linearity arises from the fact that the system is in two-phase state, which thermodynamic properties are linear combi-nations of the properties of the two phases. Data extrapolation of the PFHO melting enthalpy to zero (Fig. 3a, blue line) results in an intercept around 89 wt% PE. This indicates that about 11 wt% PFHO can penetrate into the PE packaging material under the conditions Fig. 2. DSC data on PFHO e PE (a) and PFHOePP (b) systems with different compositions (wt%) at heating rate of 10C/min (second scans). PE and PP content (in wt%) decreases
from the top to the bottom (black arrow).
Fig. 3. Enthalpy of melting for: (a) PE and PFHO (red and blue circles, respectively); (b) PP and PFHO (red and blue circles, respectively). The data were obtained from second DSC scans at a heating rate of 1C/min. Solid lines illustrate data extrapolation to zero enthalpy of melting. Confidence intervals of coefficients estimates are shown inTable S2.
Y.Z. Falk et al. / Journal of Pharmaceutical Sciences xxx (2020) 1-9 4
applied in this study. Extrapolation of the PE melting enthalpy to zero (Fig. 3a, red line) gives a value of 7 wt%, which means that this amount of PE can dissolve in PFHO in this study.
Fig. 3bshows the enthalpies of melting of PP and PFHO (red and blue symbols respectively). It demonstrates a similar behavior in
the system under the studied conditions: the enthalpy of melting of PFHO decreases linearly with increasing PP content. Extrapolation of the PFHO melting enthalpy to zero (Fig. 3b, blue line) gives an intercept about 82 wt% PP, indicating that about 18 wt% of PFHO can be absorbed into PP material. Finally, extrapolation of the enthalpy Fig. 4. Cross-polarized light microscopy images of the native PP and PP pre-treated with PFHO. Magnification is 100. Scale bar length is 100mm.
of PP melting to zero (Fig. 3b, red line) results in a value of 0.3 wt%, showing that only a small amount of PP can dissolve in PFHO. Cross e Polarized Light Microscopy
Samples of plastic packaging material and SFA were further investigated using cross-polarized light microscopy and compared to native plastic material.Fig. 4shows polarized light microscopy images of native PP and PFHOePP samples at different tempera-tures. The images demonstrate a clear difference between samples of native PP and PP pre-treated with PFHO (Fig. 4). This observation is in good agreement with the DSC data discussed above, where penetration of PFHO into plastic packaging material was concluded. Both samples are completely melted at 180 C (i.e. above PP melting) and therefore no birefringence is observed in the two lowest imagesFig. 4180C).
TGA Results
In order to determine the amount of PFHO penetrating into PE and PP packaging materials, TGA analysis was applied.Fig. 5shows TGA curves of native PE and PP and also the polymers pre-treated with PFHO for 1 week at 25, 40 and 70C. The data for native PE and PP (Fig. 5, black curves) show typical TGA degradation steps for these polymers, where thermal decomposition of the samples is observed in agreement with literature.27-29More details on the data on thermal degradation of native PE and PP materials are given in the Supporting Info (Fig. S4,Table S1).
All TGA curves, seen in Fig. 5, show similar shapes of the degradation step. However, the effect of PFHO on the plastic ma-terials is noticeable. Specifically, the plateau before the degradation step is lower for the PE and PP samples incubated in PFHO (Fig. 5a and 5b, respectively) as compared to the native polymer samples. This indicates that a certain amount of PFHO was absorbed into the PE and PP packaging materials.
The TGA data can be used to quantify the amount of PFHO absorbed by the polymers at different experimental conditions. As an example,Figure S5 (SI)shows TGA curves of PE pre-treated with PFHO using three methods for the sample preparation, seeTable 1. The process begins with mass loss of PFHO, penetrated into the packaging material and is followed by polymer degradation. This scenario is observed for the samples prepared using thefirst and third methods, where the procedure did not include heating the mixture up to 190C (Figs. S5aandS5c). However, TGA data obtained for samples prepared by the second method are different: three steps of mass loss are present (seeFig. S5bas an example).
We suggest that an extra step in mass loss observed when method 2 was used, arises from evaporation of PFHO from pores and cavities in the polymer material that appeared during heating the polymers with the liquid and subsequent cooling. In these pores the SFA is in the liquid state and therefore evaporates at lower temperature than the same substance absorbed in the polymer matrix. Hence the amount of PFHO penetrating the packaging material is estimated using the second step of mass loss for samples prepared using method 2.
Fig. 6shows TGA data of PFHO content taken up by PE and PP materials for all studied samples prepared by different methods and stored at 25, 40 and 70C. It is clearly seen that PFHO pene-trates into both plastic packaging materials. Fig. 6b shows that PFHO penetration in PP materials at higher temperatures is more pronounced than in PE material (Fig. 6a). Moreover, it is clearly seen that the PP samples incubated for 4 and 36e40 weeks (Fig. 6b, blue and red circles) absorb higher amount of PFHO than samples stored for 1 week (Fig. 6b, green circles). It can also be noticed that incu-bation at higher temperatures typically increases solvent penetra-tion into the plastic packaging materials. Fig. 6 also shows a difference in the absorbed amount of PFHO between samples prepared by different methods. In particular, melting the polymer in the SFA environment with subsequent cooling (method 2) significantly increases the amount of liquid absorbed by the poly-mer. It should however be noted that the accuracy of the TGA data in case of method 2 is not as high as in other cases since thefirst and the second steps of mass loss may overlap. Nevertheless, main focus of this study is to investigate possible interactions of SFA based formulation with PE and PP materials at ambient conditions during storage period. Our TGA data clearly show that SFA penetrates into the PE and PP packaging materials during the storage period. Ob-tained TGA data support the DSC and cross e polarized light mi-croscopy data discussed above, although the data obtained using different techniques can differ quantitatively because of difference in equilibration procedures.
Phase Diagrams of PFHOePE and PFHOePP
Constructing phase diagrams of polymer systems is a challenge. Usually polymer molecules have a distribution of chain lengths, hence polymers do not necessarily behave as single components in the thermodynamic sense. Furthermore, their phase behaviour is often dependent on the history of the sample and preparation methods. As one can see fromFigs. 1and2, melting of PE and PP does not occur as typical melting of pure one-component systems, where a single sharp peak is expected. Instead, very broad melting peaks
Fig. 5. TGA curves of (a) native PE and PE pre-treated in PFHO; (b) native PP and PP pre-treated in PFHO. Storage temperatures are labelled by subscripts. Incubation time is 1 week (method 1).
Y.Z. Falk et al. / Journal of Pharmaceutical Sciences xxx (2020) 1-9 6
are seen, indicating a gradual change of crystallinity during heating. Even though this implies that two types of domains can be present in a polymer below its melting point, we will consider it as a one-phase system due to the absence of macroscopic phase separation.
The phase diagrams of PFHO e PE and PFHOePP systems, con-structed based on DSC and TGA data are shown inFig. 7. The phases and phase transitions are outlined with respect to the system composition and temperature. The PFHOePE system comprises a large region with two phases in the temperature range of about6C and 110C, which are PFHO and PE melting
temper-atures (blue and red squares, respectively, inFig. 7). Here, PFHO is in a liquid state and PE in a solid state. However, at a PE content higher than 80e90 wt%, the PFHO e PE system exhibits only one solid phase up to 110C, where PFHO is absorbed in the packaging ma-terial (as discussed and shown above). Below PFHO melting tem-perature (blue squares,Fig. 7) the studied system exhibits a two-phase region, where two solid two-phases coexist. Above the PE melting temperature (red squares inFig. 7) the studied system consists of different phases depending on the system composition. In particular, between 0 wt% and 7 wt% PE the system shows one phase region with SFA and PE in a liquid state, where PE is dissolved in SFA. This result is obtained at high temperatures, while at lower temperatures the solubility of PE in SFA is lower. Nevertheless, further increase of PE content above 7 wt% at high temperatures
results in a two-phase area, where two liquid phases coexist. Coexistence of two liquids is the reason for the constant value of the melting temperature in this concentration range. Finally, above 79 wt% there is one phase region, where the polymer-based phase is in a liquid state.
A similar scenario of phase behavior is obtained for the PFHOePP system but with different system compositions and temperatures (Fig. 7b). As it was mentioned above, properties of solid polymers (and of equilibria involving them) can be dependent on their preparation methods. This is well illustrated in Fig. 6, where the amount of SFA in the polymer is strongly dependent on the preparation method. Theoretically, for a system behaving in an equilibrium thermodynamic way, the data inFig. 6should consti-tute the phase boundary between the solid phase and the two-phase region on the right-hand side of the two-phase diagrams (shown as dashed lines in Fig. 7). However, due to a strong dependence on the preparation method, we decided not to include these points in the phase diagrams and instead to show the approximate positions of the phase boundaries by dashed lines. Nonetheless, when comparing data obtained by the same methods, it is clear that PP absorbs more SFA than PE does, which can be explained by the fact that PP material used in this study is less crystalline and hence provides more amorphous domains that can absorb SFA molecules.
Fig. 6. TGA data for PFHO contents in PE (a) and PP (b) pre-treated at 25, 40 and 70C. Samples prepared byfirst method are shown as circles: green circles e 1 storage week, blue circles e 4 weeks, red circles e 36e40 weeks; samples prepared using the second method are shown as squares; samples prepared by third method are shown as triangles.
Fig. 7. Phase diagrams of PFHOePE (a) and PFHOePP (b), constructed from DSC and TGA data. DSC data are obtained from the second scans at a heating rate of 1C/min. Solid lines are based on experimental data, dashed lines show estimated phase boundaries for the guidance of the eye.
Obtained results summarised in the phase diagrams have to be considered, when SFA based formulations are stored in plastic bottles at ambient conditions. In particular, a product comprising a liquid formulation and a solid plastic bottle, corresponds to a two-phase state and it should remain in this state over its storage period at ambient conditions. Ideally, this two-phase area in the middle of the phase diagram should stretch along the whole system composition range, which would correspond to absence of solubi-lity of the components in each other and absence of interactions between the formulation and the package.
However, in our case there are two regions on the phase dia-gram, where interactions between SFA and plastic packaging ma-terials are observed. In particular, on the very left side of the diagram (Fig. 8, red ellipse), there is a tiny area of one liquid phase, where packaging material can dissolve in SFA. This results in a formulation containing a very small amount of dissolved compo-nents of PE or PP. On the very right side of the phase diagram (Fig. 8, red ellipse), there is one solid phase region, where SFA penetrates into the plastic bottle.
In general, it can be concluded that construction of phase dia-grams using DSC, cross e polarized light microscopy and TGA is a suitable method for a generic screening in feasibility studies and for the modelling of packaging systems during early development. The obtained data is later applied for the selection of materials which are then tested, refined and verified in various approaches, this can include stability, extractable and leachable studies, following pharmacopoeial guidance. In later stages of development, it is mandatory to conduct testing with specific, sensitive analytical methods to ensure quality and safety of the final drug product. Furthermore, comprehensive interaction studies have to be per-formed under conditions representative for the medicinal product or medical device using thefinal composition and quality, the final container closure system andfill volumes.
Conclusions
Interactions of PFHO with PE and PP plastic packaging materials were investigated and characterised by DSC, cross e polarized light microscopy and TGA using varied sample preparation methods.
As anticipated, DSC measurements demonstrate interactions of PFHO with PE and PP materials. In particular, PFHO tends to lower the melting temperature of PE and PP. In addition, cross-polarized
light microscopy of PP under heating demonstrates a difference between untreated PP and PP pre-treated in the presence of PFHO. Second scans of DSC experiments were used to characterise equilibrium interactions of the plastic materials with SFA. Extrap-olation of the melting enthalpy data indicates that upon heating relatively small amounts: around 0.3 wt% of PP and approximately 7 wt% of PE can dissolve in PFHO, suggesting that PP might be a better packing material for PFHO compared to PE.
On the other hand, both plastic materials show substantial ab-sorption of SFA. In particular, 11 wt% and 18 wt% of PFHO can be absorbed by PE and PP materials respectively at temperatures close to the melting temperature of the SFA. As expected, experiments with absorption of SFA by original untreated plastic materials show lower absorbed amounts. In particular, TGA measurements indicate absorption of approximately 1.2 wt% and 5 wt% of PFHO by pieces of PE and PP respectively after four weeks equilibration at 25C.
Phase diagrams of PFHOePE and PFHOePP systems were con-structed based upon DSC data, where phases and phase transitions are outlined with respect to temperature and system composition. Development of such a phase diagrams can be a useful tool in characterization of interactions of SFA with plastics intended for use in ophthalmic packaging systems.
Based on the presented data we conclude that comprehensive studies of interactions between PFHO and PE and PP are required if these materials are used in packaging of PFHO-containing formulations.
Supporting Information
Supplementary DSC, TGA and WAXS data are available in the Supporting Information.
Acknowledgments
This study wasfinancially supported by Novaliq GmbH (Hei-delberg, Germany) as a joint research project. Authors are thankful to Peter Falkman for the help with WAXD measurements. Appendix A. Supplementary Data
Supplementary data to this article can be found online at
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