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Systemic analysis about residual chloroform in PLLA films

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Current Directions in Biomedical Engineering
From the journal Current Directions in Biomedical Engineering Volume 2 Issue 1

Abstract

Toxic volatile organic chemicals (VOCs), such as chloroform, are widely used in polymer manufacture in the field of implants and polymeric drug carriers. Several processes have to be carried out in order to remove toxic VOCs for patient safety without changing the thermal characteristics of the polymers. Therefore, we analyze the common commercial implant polymer poly(L-lactide) (PLLA) and screen different annealing- and rinsing processes considering influence on their morphology and thermal properties. For PLLA a rinsing step followed by annealing results in acceptable chloroform contents according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) recommendations. Annealing processes reveal the lowest chloroform content after one day, which did not further decrease significantly with extended annealing time.

Keywords: annealing; implant; PLLA; residual chloroform; rinsing

1 Introduction

Volatile organic chemicals (VOCs), such as chloroform, are often used in the manufacture of polymeric implants or polymer based drug delivery systems. The well-considered choice of the solvents is relevant for the physical polymer characteristics such as crystallinity and drug release profiles. Hence, a change of solvent is most likely not feasible. Normally, practical manufacture techniques do not completely remove the solvents. However, acceptable amounts of residual VOCs in polymeric implants should be reached for the safety of the patients.

Therefore we analyzed our film manufacture of poly(L-lactide) (PLLA) according to the residual chloroform in the films because they are widely used in the implant field. Moreover we performed a screening to test several rinsing and annealing procedures and analyzed their impact on the residual chloroform, morphology and thermal properties. Conditions were chosen to not alter thermal and morphological characteristics of the films. We aimed for a residual chloroform concentration of 0.006 mass percent of the polymer according to the recommendations of ICH Harmonised Tripartite Guideline 4 (2009) [1].

2 Material and methods

2.1 Film preparation

The polymer film was prepared using the following procedure: 0.75 g PLLA (RESOMER® L210, Mw = 380.000, Evonik, Germany) was dissolved in 25 ml chloroform and the resulting solution was poured into a glass petri dish (Ø = 9 cm). The solvent was allowed to evaporate until a 100 μm thick film had formed, which was cut from the petri dish.

2.1.1 Annealing procedure

After film preparation several annealing and rinsing procedures were screened for PLLA. First an annealing process was started using a vacuum drying cabinet (UM20, Memmert GmbH & Co KG, Deutschland) at 40°C or 80°C with 40 mbar and the chloroform concentration was determined after several time points (see Table 1).

Table 1:

Temperature and time points of chloride determination during annealing processes of PLLA.

PolymerTemperatureTime point of measure (day)
PLLA40°C1234567
80°C1234567

2.1.2 Rinsing procedure

Additional rinsing steps of the films were performed before annealing to reach the recommended chloroform concentration. In a first step methanol was used followed by a rinsing step with ultrapure water. Each rinsing step was performed for 24 h. Different rinse combinations were screened (see Table 2). Best conditions of the annealing screening were used after each rinsing procedure.

Table 2:

Screening of different rinse processes. All rinsing steps are performed for 24 h. Annealing process for PLLA was 24 h at 40°C.

Process no.Step no.
12345
1MethanolWaterAnnealing
2MethanolMethanolWaterAnnealing
3MethanolMethanolWaterWaterAnnealing

2.2 Trace chloride analyses

The samples were weighed using a special accuracy balance (UMX 5, Mettler Toledo, Switzerland) prior to determination of chlorine content. A TOX-2100H Total Chlorine Analyzer (Mitsubishi Chemical Analytech Co., LTD, Japan) was used were weighed samples were combusted in an argon/oxygen atmosphere. The resulting hydrogen chloride was led into a titration cell where it was automatically titrated by silver ions generated coulometrically. The amount of chlorine was calculated by the quantity of electricity required for the titration.

2.3 Morphology

The morphology of the PLLA specimens was examined with a SEM QUANTA FEG 250 (FEI Company, Germany). The samples were fixed on aluminium trays with conductive tape. The images were taken at various magnifications.

2.4 Differential scanning calorimetry (DSC)

Melting behaviour was measured using a DSC 1 Stare sys-tem (Mettler Toledo, Switzerland). The specimens of n = 5 films per subgroup were heated at a rate of 10 K/min and cooled down at a rate of 20 K/min operating under nitrogen pressure. The sample weights were in the range of 3–6 mg. The data were analysed with respect to the degree of crystallinity (χ). The heats of fusion and crystallization were quantitatively evaluated by determining the endothermic and exothermic peak areas. For the latter a value of χ100 = 93.7 J/g [2] for totally crystalline PLLA was used.

2.5 Statistical analysis

Statistical analyses of data were performed using a two-tailed t-test according to [3]. The experimental data were shown as mean ± standard deviation. The p-value of <0.05 was considered as statistically significant.

3 Results

Annealing processes reveal lower residual chloroform at 80°C then 40°C (see Table 3).

Table 3:

Chloroform content in PLLA films after annealing process by 40°C and 80°C at 40 mbar. n = 5.

Time (day)Chloroform (m%)
40°C80°C
012.88 ± 1.450312.88 ± 1.4503
15.70 ± 0.69860.99 ± 0.1670
25.12 ± 1.11330.61 ± 0.0695
35.93 ± 0.81441.54 ± 0.3971
44.35 ± 0.80621.88 ± 0.1192
54.58 ± 0.88761.58 ± 0.1163
64.86 ± 0.55470.76 ± 0.2888
75.2 ± 0.47930.42 ± 0.0455

After the first day a significant decrease of residual chloroform for PLLA is observed. There is no further significant decrease with increasing annealing time. Additionally, in contrast to 40°C, ringlike cavities at 80°C annealing process with a growing diameter over annealing time are determined (see Figure 2).

Due to high residual chloroform after the annealing process we also performed a rinsing process screening before annealing (see Figure 1). Unfortunately, ringlike cavities whose diameters grow with increasing rinsing steps occur (see Figure 2). Measured crystallinity after rinsing and annealing is 34.47 ± 6.29%.

Figure 1: Chloroform content in PLLA after rinsing and annealing processes at 40°C at 40 mbar for 1 day. n = 5.
Figure 1:

Chloroform content in PLLA after rinsing and annealing processes at 40°C at 40 mbar for 1 day. n = 5.

Figure 2: ESEM pictures of PLLA films at 1000× magnification. PLLA after film preparation (A), after 1 day annealing at 80°C (B), after 7 days annealing at 80°C (C), after rinsing process 1 (D), after rinsing process 2 (E) and after rinsing process 3 (F). HV, high voltage; det, detector; LFD, large field detector; WD, working distance; HFE, horizontal field width; mag, magnification.
Figure 2:

ESEM pictures of PLLA films at 1000× magnification. PLLA after film preparation (A), after 1 day annealing at 80°C (B), after 7 days annealing at 80°C (C), after rinsing process 1 (D), after rinsing process 2 (E) and after rinsing process 3 (F). HV, high voltage; det, detector; LFD, large field detector; WD, working distance; HFE, horizontal field width; mag, magnification.

4 Discussion

Heat temperature was chosen related to the glass transition temperature of the polymers.

Nevertheless, it is not possible to reach the recommended chloroform content [1] by an annealing process only, neither at 40°C nor at 80°C. The lowest residual chloroform is observed after 1 day of annealing. Increasing annealing time results in non-significant lower chloroform content. Therefore additional rinsing procedures have been screened. The results reveal a high impact of methanol in terms of decreasing the chloroform content [4]. The following rinsing process with water was performed to reduce residual methanol.

The results of the crystallinity determined by DSC measurements are similar to reported crystallinities of PLLA at 39.7% [5].

In contrast to the annealing process at 40°C, morphological changes are visible after the annealing process at 80°C and also after the rinsing procedures (see Figure 2). Changes in microstructure are induced by the solvent, which acts as a plasticizer. TG of PLLA is shifted to lower temperature in the presence of a high amount of chloroform [6], so the amorphous regions of PLLA are in the liquid phase and molecular chains are more flexible during the rinsing and annealing process. Hence, crystal growth can occur. The final treatment process is rinsing process 3 (see Table 2) and annealing at 40°C and 40 mbar for 1 day to remove the residual chloroform with marginal effects on morphology and thermal properties. However, due to the resulting morphological changes further investigations to improve rinsing processes are disclaimed.

Acknowledgement

The authors thank Andrea Rohde, Caroline Dudda and Martina Schröder for their practical assistance. Financial support by the Federal Ministry of Education and Research (BMBF) within RESPONSE “Partnership for Innovation in Implant Technology” is gratefully acknowledged.

Author’s Statement

Research funding: The author state no funding involved. Conflict of interest: Authors state no conflict of interest. Material and Methods: Informed consent: Informed consent is not applicable. Ethical approval: The conducted research is not related to either human or animal use.

References

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Published Online: 2016-9-30
Published in Print: 2016-9-1

©2016 Michael Teske et al., licensee De Gruyter.

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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https://doi.org/10.1515/cdbme-2016-0014
Keywords for this article
annealing; implant; PLLA; residual chloroform; rinsing
Creative Commons
BY-NC-ND 4.0

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  127. Influence of different test gases in a non-destructive 100% quality control system for medical devices
  128. Device development guided by user satisfaction survey on auricular vagus nerve stimulation
  129. Empirical assessment of the time course of innovation in biomedical engineering: first results of a comparative approach
  130. Effect of left atrial hypertrophy on P-wave morphology in a computational model
  131. Simulation of intracardiac electrograms around acute ablation lesions
  132. Parametrization of activation based cardiac electrophysiology models using bidomain model simulations
  133. Assessment of nasal resistance using computational fluid dynamics
  134. Resistance in a non-linear autoregressive model of pulmonary mechanics
  135. Inspiratory and expiratory elastance in a non-linear autoregressive model of pulmonary mechanics
  136. Determination of regional lung function in cystic fibrosis using electrical impedance tomography
  137. Development of parietal bone surrogates for parietal graft lift training
  138. Numerical simulation of mechanically stimulated bone remodelling
  139. Conversion of engineering stresses to Cauchy stresses in tensile and compression tests of thermoplastic polymers
  140. Numerical examinations of simplified spondylodesis models concerning energy absorption in magnetic resonance imaging
  141. Principle study on the signal connection at transabdominal fetal pulse oximetry
  142. Influence of Siluron® insertion on model drug distribution in the simulated vitreous body
  143. Evaluating different approaches to identify a three parameter gas exchange model
  144. Effects of fibrosis on the extracellular potential based on 3D reconstructions from histological sections of heart tissue
  145. From imaging to hemodynamics – how reconstruction kernels influence the blood flow predictions in intracranial aneurysms
  146. Flow optimised design of a novel point-of-care diagnostic device for the detection of disease specific biomarkers
  147. Improved FPGA controlled artificial vascular system for plethysmographic measurements
  148. Minimally spaced electrode positions for multi-functional chest sensors: ECG and respiratory signal estimation
  149. Automated detection of alveolar arches for nasoalveolar molding in cleft lip and palate treatment
  150. Control scheme selection in human-machine- interfaces by analysis of activity signals
  151. Event-based sampling for reducing communication load in realtime human motion analysis by wireless inertial sensor networks
  152. Automatic pairing of inertial sensors to lower limb segments – a plug-and-play approach
  153. Contactless respiratory monitoring system for magnetic resonance imaging applications using a laser range sensor
  154. Interactive monitoring system for visual respiratory biofeedback
  155. Development of a low-cost senor based aid for visually impaired people
  156. Patient assistive system for the shoulder joint
  157. A passive beating heart setup for interventional cardiology training
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