A medicinal liquid strip packaging composite film and a preparation method thereof

Abstract

This invention relates to the field of liquid packaging composite film preparation technology, and particularly to a pharmaceutical liquid strip packaging composite film and its preparation method. The composite film, from the outside to the inside, comprises: a PET printing layer, an adhesive layer, a PET reinforcing layer, a hybrid adhesive transition layer, a metal barrier layer, another adhesive layer, and a corona-treated CPP heat-sealing layer. The method includes forming a first composite substrate by combining the CPP heat-sealing layer and the metal barrier layer; determining the chemical bonding structure stability of the first composite substrate and re-determining the target bonding temperature; bonding the metal barrier layer and the PET reinforcing layer to form a second composite substrate; determining the crosslinking quality of the hybrid adhesive transition layer and determining the target curing time of the composite film; bonding the second composite substrate and the PET printing layer to form the composite film; determining the strip-pack sealing performance; and determining the target mass fraction of silica in the CPP heat-sealing layer. This invention improves the long-term resistance to pharmaceutical liquid erosion and the sealing durability of the composite film.

Description

Technical Field

[0001] This invention relates to the field of liquid packaging composite film preparation technology, and in particular to a pharmaceutical liquid strip packaging composite film and its preparation method. Background Technology

[0002] Pharmaceutical liquid strip packaging is widely used in the independent packaging of pharmaceutical products such as oral liquids, topical medications, and solution preparations. It has stringent requirements for the oxygen and water vapor barrier properties, resistance to chemical erosion by pharmaceutical solutions, interlayer interface adhesion stability, and heat-sealing integrity of the packaging composite film. Existing pharmaceutical strip packaging composite films are mostly made by simply stacking PET, aluminum foil, and ordinary CPP film. The interlayer is generally directly bonded with a general two-component polyurethane adhesive. The metal barrier layer and the polymer film layer rely only on physical adsorption and lack chemical bonding. Moreover, the conventional composite preparation process does not perform adaptive modification treatment on the CPP surface and the metal layer surface. The adhesive is prone to hydrolysis and swelling under long-term immersion in pharmaceutical solutions containing ethanol, inorganic salts, and surfactants. Problems such as local delamination and uneven adhesion distribution at the interlayer interface are prone to occur. It is difficult to meet the high standards of use for pharmaceutical liquids during long-term storage, such as preventing leakage, oxidation, light deterioration, and aging of pharmaceutical solutions.

[0003] Chinese Patent Application Publication No. CN115635754A discloses a single-dose liquid pharmaceutical composite film and its manufacturing process. The single-dose liquid pharmaceutical composite film comprises, from top to bottom, a PET layer, an aluminum foil layer, a polyamide layer, and a polyethylene layer. The PET layer and aluminum foil layer, the aluminum foil layer and polyamide layer, and the polyamide layer and polyethylene layer are all bonded together using a two-component polyurethane adhesive. An ink layer is printed on the PET layer near the aluminum foil layer. This invention combines PET with montmorillonite, improving the barrier properties of the pharmaceutical composite film, and utilizes silver ions to enhance its antibacterial properties. Therefore, the pharmaceutical composite film prepared in this application possesses high barrier properties and antibacterial properties, ensuring a safe production environment.

[0004] The existing technology also has the following problems: the existing pharmaceutical liquid packaging composite film layers mostly rely on physical adsorption to achieve adhesion, lacking a stable chemical bonding structure. The adhesive is easily hydrolyzed and swollen by long-term immersion and erosion of the drug liquid containing ethanol, inorganic salts and surfactants, which can easily cause interlayer interface peeling and form micro-leakage channels, resulting in poor long-term drug liquid erosion resistance and sealing durability of the composite film. Summary of the Invention

[0005] To address this, the present invention provides a pharmaceutical liquid strip packaging composite film and its preparation method, which overcomes the problems of existing pharmaceutical liquid packaging composite films where the interlayer bonding relies solely on physical adsorption, lacking a stable chemical bond structure, and the adhesive being easily hydrolyzed and swollen by long-term immersion and erosion of pharmaceutical liquids containing ethanol, inorganic salts, and surfactants, easily causing interlayer interface peeling and forming microscopic leakage channels, thus resulting in poor long-term resistance to pharmaceutical liquid erosion and poor sealing durability of the composite film.

[0006] To achieve the above objectives, in one aspect, the present invention provides a method for preparing a pharmaceutical liquid strip packaging composite film, comprising: The corona-treated CPP heat-sealing layer and the metal barrier layer are bonded together with adhesive, and the first composite substrate is immersed in simulated drug solution. The stability of the chemical bonding structure is determined based on the coefficient of variation of the carbonyl absorption peak intensity of the adhesive layer of the first composite substrate, and the target composite temperature of the first composite substrate is re-determined. The metal barrier layer is combined with the PET reinforcement layer to form a second composite substrate; The crosslinking quality of the hybrid adhesive transition layer is determined based on the surface potential half-life of the second composite substrate treated with a high-voltage electrostatic field, and the target curing time of the composite film is determined. The PET reinforcement layer of the second composite substrate is laminated with the PET printing layer to form a composite film; The sealing performance of the strip package was determined based on the fluorescent leakage region characteristics of the heat-sealed area of ​​the composite film after simulated filling, and the target mass fraction of silica in the CPP heat-sealing layer was determined.

[0007] Furthermore, the coefficient of variation of the carbonyl absorption peak intensity is determined based on the carbonyl peak area in a preset wavelength range in the infrared spectrum, and is used to characterize the curing crosslinking degree and distribution uniformity of the two-component polyurethane adhesive.

[0008] Furthermore, the chemical bonding structure is deemed unsatisfactory, which is determined based on the fact that the coefficient of variation of the carbonyl absorption peak intensity is greater than a preset coefficient of variation.

[0009] Furthermore, the target composite temperature is determined based on the coefficient of variation of the carbonyl absorption peak intensity and a preset coefficient of variation, in order to regulate the curing uniformity of the two-component polyurethane adhesive.

[0010] Furthermore, the crosslinking quality of the hybrid adhesive transition layer is unqualified, which is determined based on the surface potential half-life being less than a preset half-life.

[0011] Furthermore, the surface potential half-life is determined based on the surface potential decay curve of the PET reinforcement layer, and is used to characterize the crosslinking density and curing uniformity of the hybrid adhesive transition layer.

[0012] Furthermore, the target curing time is determined based on the preset half-life and the surface potential half-life, and is used to regulate the crosslinking quality of the hybrid adhesive transition layer.

[0013] Furthermore, the fluorescent leakage area feature includes the leakage area ratio and the leakage path width, wherein the leakage area ratio is the percentage of the pixel area of ​​the fluorescent leakage area to the total area of ​​the heat-sealed area. The leakage path width is the maximum width value in the normal direction along the extension direction of the leakage path in the fluorescent leakage area.

[0014] Furthermore, the failure of the strip package to meet the sealing requirements is determined based on the fact that the leakage area ratio is greater than a preset area ratio, or the leakage path width is greater than a preset width.

[0015] On the other hand, the present invention also provides a pharmaceutical liquid strip packaging composite film, which, from the outside to the inside, consists of: a PET printing layer, an adhesive layer, a PET reinforcing layer, a hybrid adhesive transition layer, a metal barrier layer, an adhesive layer, and a CPP heat-sealing layer treated with corona discharge.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: by performing corona surface activation on the CPP heat-sealing layer and coating the metal barrier layer with a silane coupling agent primer, a covalent bond connection system of hydroxyl condensation and urethane bonding is constructed at the interface. Combined with the physical anchoring effect formed by surface roughening, weak sites of physical adsorption are eliminated, the penetration and diffusion of ethanol, water molecules and surfactants in the drug solution along the interface are blocked, and interface debonding and micro-peeling are inhibited, thereby improving the long-term drug solution erosion resistance and sealing durability of the composite film.

[0017] Furthermore, this invention uses the coefficient of variation of the carbonyl absorption peak intensity of the polyurethane adhesive layer as a quantitative characterization basis for interfacial bonding uniformity, and optimizes the leveling and curing kinetics of the adhesive by adaptively adjusting the composite temperature. Under existing fixed processes, the coefficient of variation of the carbonyl absorption peak intensity of the adhesive layer is as high as 22%, resulting in extremely poor interfacial bonding uniformity. However, this invention can precisely control the coefficient of variation to within 13% through adaptive temperature control, enabling the adhesive layer to form a continuous and dense homogeneous structure, eliminating local accumulation, defects, and micropores, alleviating interfacial stress concentration, and increasing the interlayer peel strength retention rate after 72 hours of immersion in the solution by more than 20%. It also significantly slows down the hydrolysis and swelling rate of the adhesive in the solution, thereby improving the long-term resistance to chemical corrosion and the sealing durability of the composite film.

[0018] Furthermore, this invention utilizes the structure-property relationship between the surface potential half-life and the crosslinking density of the adhesive to provide real-time feedback on the curing degree of the adhesive layer using surface potential decay data and precisely adjust the curing time. Under existing fixed-time curing processes, the surface potential half-life of the hybrid adhesive layer is only 85s, resulting in insufficient crosslinking and curing. However, this invention can increase the half-life to over 125s through adaptive time control, effectively increasing the crosslinking density of the adhesive layer by 47%. This promotes the formation of a highly crosslinked three-dimensional network structure in the epoxy-polyurethane hybrid adhesive, enhances the molecular chain binding ability and charge trap density, strengthens the adhesive layer's resistance to small molecule plasticization and ion erosion, and effectively prevents the penetration of the liquid into the metal interface, thus preventing corrosion and delamination. This improves the long-term resistance to liquid erosion and the sealing durability of the composite film.

[0019] Furthermore, this invention employs a hydroxyl polyester main agent matched with an isocyanate curing agent and an epoxy-polyurethane hybrid synergistic adhesive molecule design. This hybrid compound system can take into account the advantages of epoxy resin's high strength and corrosion resistance and polyurethane's flexibility and adaptability, so that each layer of the adhesive system has high bonding strength, hydrolytic stability and interfacial stress buffering capacity, achieving a balance between rigid support and toughness buffering, effectively reducing the interlayer strength attenuation under long-term chemical immersion. Combined with the invention's unique control process, the material performance advantages are further amplified, thereby improving the long-term chemical erosion resistance and sealing durability of the composite film.

[0020] Furthermore, this invention adaptively adjusts the silica particle content of the modified CPP heat-sealing layer based on fluorescence leakage detection characteristic data. Under existing fixed silica addition processes, the average batch leakage rate of composite membranes is as high as 2.1%, with numerous microscopic defects in the heat-sealing process and a high risk of seal failure. However, this invention, by precisely controlling the silica content, can control the average batch leakage rate to within 0.18%, reducing leakage defects by more than 91%. This effectively eliminates microscopic voids and through-leakage channels at the heat-sealing interface, blocks the capillary penetration and diffusion paths of the liquid, and significantly improves the structural integrity and long-term sealing reliability of the heat-sealed area. This, in turn, enhances the long-term resistance to liquid erosion and the sealing durability of the composite membrane. Attached Figure Description

[0021] Figure 1 This is a flowchart illustrating the preparation method of the pharmaceutical liquid strip packaging composite film according to an embodiment of the present invention; Figure 2 A flowchart for determining the chemical bonding structure stability of the first composite substrate in an embodiment of the present invention; Figure 3 This is a flowchart illustrating the process of determining the crosslinking quality of the hybrid adhesive transition layer in an embodiment of the present invention. Figure 4 This is a flowchart for determining the sealing performance of the strip package in an embodiment of the present invention. Detailed Implementation

[0022] To make the objectives and advantages of the present invention clearer, the present invention will be further described below with reference to embodiments; it should be understood that the specific embodiments described herein are merely for explaining the present invention and are not intended to limit the present invention.

[0023] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings. Those skilled in the art should understand that these embodiments are merely illustrative of the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0024] Please see Figure 1 As shown, it is a flowchart of the preparation method of the pharmaceutical liquid strip packaging composite film according to an embodiment of the present invention.

[0025] The method for preparing a pharmaceutical liquid strip packaging composite film according to an embodiment of the present invention includes: Step S1: The corona-treated CPP heat-sealing layer and the metal barrier layer are bonded together with adhesive, and the first composite substrate is immersed in simulated drug solution. Step S2: Determine the chemical bonding structure stability based on the coefficient of variation of the carbonyl absorption peak intensity of the adhesive layer of the first composite substrate, and redetermine the target composite temperature of the first composite substrate. Step S3: The metal barrier layer is combined with the PET reinforcement layer to form a second composite substrate; Step S4: Determine the crosslinking quality of the hybrid adhesive transition layer based on the surface potential half-life of the second composite substrate treated with a high-voltage electrostatic field, and determine the target curing time of the composite film. Step S5: The PET reinforcement layer of the second composite substrate is laminated with the PET printing layer to form a composite film; Step S6: Determine the sealing performance of the strip package based on the fluorescent leakage area characteristics of the heat-sealed area of ​​the composite film after simulated filling, and determine the target mass fraction of silica in the CPP heat-sealing layer.

[0026] In this embodiment, during the preparation of the first composite substrate, the composite side of the CPP heat-sealing layer is first modified by surface oxidation using corona treatment. The CPP film is passed through the discharge gap between the electrode and the grounding roller at a speed of 30m / min to 150m / min, while a high-frequency high voltage of 10kV to 30kV and a frequency of 15kHz to 30kHz is applied simultaneously to ionize the air and generate corona discharge, making the surface tension of the CPP heat-sealing layer ≥42dyn / cm. Simultaneously, a silane coupling agent primer is coated onto the composite side of the metal barrier layer, with a coating thickness of 0.2μm to 0.5μm. The silane coupling agent can be KH-550 or KH-560. 1%-5% by mass of silane monomer is slowly added to a mixed solution of ethanol and water, and hydrolyzed for 30min-60min under stirring to obtain a transparent or semi-transparent silane coupling agent primer, wherein the volume ratio of ethanol to water is 7:3 to 8:2.

[0027] Specifically, high-energy particles in the plasma generated by the discharge bombard the film surface, breaking the polymer molecular chains and introducing polar groups such as hydroxyl and carbonyl groups, while simultaneously increasing surface roughness. The hydrolyzed silane forms silanol (Si-OH), which can undergo a condensation reaction with the hydroxyl groups on the surface of the metal barrier layer. Corona treatment activates the CPP heat-sealing layer surface, and the silane coupling agent organically binds the metal barrier layer surface. Together, these two processes enhance the adhesion of the CPP / metal interface from physical adhesion to a dual effect of chemical bonding and physical anchoring, resisting long-term erosion from water, ethanol, and surfactants in the solution.

[0028] In practice, the composite side refers to the surface of each material participating in the current composite step. For the CPP heat-sealing layer, the composite side is only the side opposite to the metal barrier layer; for the metal barrier layer, the composite side is the side opposite to the CPP heat-sealing layer.

[0029] Specifically, the first composite substrate comprises, from one side to the other, a corona-treated CPP heat-sealing layer, an adhesive layer, and a metal barrier layer. The adhesive layer, located between the CPP heat-sealing layer and the metal barrier layer, is formed by coating and drying a two-component polyurethane adhesive. The dry basis coating weight of the adhesive layer is 1.5 g / m². 2 ~4.0g / m 2 This achieves a strong bond between the CPP heat-sealing layer and the metal barrier layer; On the composite side of the metal barrier layer, that is, the side opposite to the CPP heat-sealing layer, a layer of silane coupling agent primer is pre-coated between the surface of the metal barrier layer and the adhesive layer to enhance the chemical bonding between the metal surface and the adhesive, thereby improving the long-term stability against chemical immersion. The metal barrier layer, serving as the intermediate barrier layer in the composite film, can be an aluminum foil with a thickness of 6μm to 9μm, but is not limited to aluminum foil; it can also be other metal foils with high barrier properties. The metal barrier layer provides complete protection against oxygen, water vapor, and light, preventing leakage and deterioration of the pharmaceutical solution.

[0030] Specifically, the two-component polyurethane adhesive consists of a hydroxyl-type main agent and an isocyanate-type curing agent. By weight, the main agent formulation includes: 100 parts saturated polyester polyol, 35-45 parts ethyl acetate, 5-10 parts anhydrous ethanol, 0.3-0.8 parts hydrolysis stabilizer, and 0.1-0.3 parts wetting and leveling agent; The main agent meets the following performance indicators: hydroxyl value 55~65mgKOH / g, solid content 55%±2%, and viscosity 1800~2500mPa·s at 25℃.

[0031] The curing agent formulation comprises, by weight, 100 parts of IPDI trimer isocyanate and 40-50 parts of ethyl acetate; The curing agent performance indicators meet the following requirements: NCO mass fraction 18%~20%, solid content 60%±2%, and viscosity 800~1200mPa·s at 25℃.

[0032] When mixing the adhesive on-site, the mass ratio of the main agent to the curing agent is 100:18-25. After mixing, the adhesive is diluted with ethyl acetate to adjust the working solids content of the adhesive to 30%-35% for coating.

[0033] Specifically, the preparation steps of the first composite substrate are as follows: a silane coupling agent primer is coated onto the composite side of the metal barrier layer, and dried in a three-stage drying tunnel to form a primer layer. The temperature of the first stage is 50℃~60℃, the temperature of the second stage is 60℃~70℃, and the temperature of the third stage is 70℃~80℃. A polyurethane adhesive is applied on the surface of the metal barrier layer or directly through the first dry composite unit, and dried in the drying tunnel to remove the solvent. The corona-treated CPP heat-sealing layer and the metal barrier layer coated with adhesive are bonded together under the action of heating rollers and pressure rollers, and cooled by cooling rollers at a temperature of 10℃~15℃ before being wound up to form the first composite substrate. The temperature of the heating roller is the composite temperature of the first composite substrate, with a temperature range of 70℃~90℃, a composite pressure of 0.4MPa~0.8MPa, and a composite speed of 60m / min~120m / min.

[0034] Specifically, at least three rectangular samples, approximately 10 mm wide and 30 mm long, were cut from the first composite substrate. Each sample was immersed in a container filled with simulated pharmaceutical solution and soaked at 40°C for 72 hours. Afterward, the samples were removed, gently rinsed three times with purified water to remove residual solution, and then allowed to air dry at room temperature. The samples were then embedded using epoxy resin embedding agent. The samples were placed vertically at the bottom of the embedding mold, with the cross-sectional direction perpendicular to each layer plane facing upward. After curing, the embedding block was trimmed to expose the complete cross-section of the first composite substrate. After slicing, Fourier transform infrared microscopy was used to collect infrared spectra point-by-point along the direction perpendicular to the CPP / metal interface, with a scanning range of 650 cm⁻¹. -1 ~4000cm -1 The resolution is 4cm. -1 The scanning step size was 1 μm, the number of scans was 32, and 10 to 15 measurement points were collected for each scan line. One infrared spectrum was obtained for each measurement point. At least 3 scan lines with different cross-sectional positions were obtained, and a total of no less than 30 spectra were obtained. The simulated drug solution was an aqueous solution containing 5% ethanol, 0.9% NaCl and 0.5% Tween-80.

[0035] In this embodiment of the invention, the coefficient of variation of the carbonyl absorption peak intensity is determined based on the carbonyl peak area in a preset wavelength range in the infrared spectrum, and is used to characterize the curing crosslinking degree and distribution uniformity of the two-component polyurethane adhesive.

[0036] As a preferred embodiment, the infrared spectrum is corrected using the stretching vibration peak position of -CH2- as a reference peak; Extract the 1700 cm⁻¹ from the corrected infrared spectrum. -1 ~1760cm -1 Within the interval, several consecutive measurement points with carbonyl peak areas located in the adhesive layer region that are greater than or equal to a preset area; The percentage of the standard deviation to the average value of the carbonyl peak area at several consecutive measurement points is determined as the coefficient of variation of the carbonyl absorption peak intensity.

[0037] In an optional embodiment of the present invention, the preset area value is three times the average CPP background value. The average CPP background value is determined by taking multiple measurement points in the region more than 10 μm away from the interface within the CPP heat-sealing layer for each cross-sectional scan line, and taking the average carbonyl peak area of ​​the multiple measurement points as the average CPP background value.

[0038] In this embodiment of the invention, CPP itself does not contain carbonyl groups, and its carbonyl peak area is close to 0, with only background noise present. However, the two-component polyurethane adhesive forms urethane bonds (-NH-COO-) after curing, which contain carbonyl groups (C=O). The stretching vibration absorption peak of the carbonyl group appears at 1700 cm⁻¹. -1 ~1760cm -1The center is usually at 1730cm -1 Nearby, therefore 1700cm was chosen. -1 ~1760cm -1 The area of ​​the carbonyl peak within the range.

[0039] In this embodiment of the invention, to eliminate interference from physical factors such as uneven adhesive layer thickness, substrate absorption differences, spectral baseline drift, and optical path changes during infrared detection, and to ensure that the carbonyl peak area measurement results only reflect the curing crosslinking degree and distribution uniformity of the two-component polyurethane adhesive, The stretching vibration peak position is used as the reference peak in the corrected infrared spectrum. These are saturated carbon-hydrogen bonds, belonging to chemically inert groups. They do not participate in any chemical changes such as polyurethane curing crosslinking, chemical hydrolysis, or thermal processing. Their peak position, shape, and absorption intensity remain stable before and after detection, making them an ideal internal standard. Furthermore... The peak of the stretching vibration is fixed at 2800–3000 cm⁻¹. -1 Within this range, the peaks are sharp and have high signal intensity, completely separated from carbonyl characteristic peaks with no spectral overlap or interference, allowing for precise calibration of the spectral baseline and absorption intensity. Furthermore, The structure is widely present in two-component polyurethane adhesives, CPP heat-sealing layers and PET substrates. The signal can penetrate through the interior of the adhesive layer and the interface region. After correction, the infrared spectrum can effectively eliminate irrelevant variables such as thickness and substrate differences, ensuring that the carbonyl peak area after correction truly represents the stability of the chemical bonding structure between the adhesive and the film.

[0040] In this embodiment of the invention, the degree of curing and cross-linking of the two-component polyurethane adhesive and its uniform distribution directly determine the bonding strength and resistance to chemical erosion between the CPP heat-sealing layer and the metal barrier layer. The carbonyl group is a characteristic functional group of polyurethane, and its infrared absorption peak area is proportional to the relative content of the adhesive at the corresponding measurement point. A small coefficient of variation for the carbonyl absorption peak intensity indicates that the carbonyl peak areas at each measurement point are similar, the adhesive coating is uniform, the composite temperature and pressure are suitable, and the adhesive layer forms a continuous and dense adhesive structure, effectively resisting the penetration and chemical erosion of the chemical solution, ensuring reliable long-term interfacial bonding quality. A large coefficient of variation for the carbonyl absorption peak intensity indicates uneven distribution of the adhesive layer, possibly due to local accumulation with excessively large peak areas, or local absence with excessively small peak areas. In areas where adhesive is missing, the CPP and metal layer rely only on weak physical adsorption, making them prone to interfacial delamination under the stress of drug immersion or subsequent heat sealing and filling. Furthermore, stress concentration occurs at the boundary between the adhesive accumulation area and the missing area, accelerating crack initiation and propagation. In addition, uneven adhesive distribution may be accompanied by micropores or unwetted areas, allowing water, ethanol, and surfactants in the drug solution to penetrate to the interface along these channels and further degrade the adhesive.

[0041] Please see Figure 2As shown, it is a flowchart for determining the chemical bonding structure stability of the first composite substrate in an embodiment of the present invention.

[0042] In a preferred embodiment, if the coefficient of variation of the carbonyl absorption peak intensity of the adhesive layer of the first composite substrate after being soaked in simulated drug solution is less than or equal to a preset coefficient of variation, then the chemical bonding structure stability of the first composite substrate is determined to be qualified; if the coefficient of variation of the carbonyl absorption peak intensity is greater than the preset coefficient of variation, then the chemical bonding structure stability of the first composite substrate is determined to be unqualified.

[0043] In an optional embodiment of the present invention, the preset coefficient of variation is set to 15%. Statistical analysis of historical preparation data from at least 50 batches of composite membranes revealed that when the coefficient of variation for the carbonyl absorption peak intensity is less than or equal to 15%, the peel strength retention rate after 72 hours of immersion in the simulated drug solution is approximately 79%, and the average batch leakage rate is less than or equal to 0.2%. However, when the coefficient of variation exceeds 15%, the peel strength retention rate drops below 70%, and the average batch leakage rate rises sharply to over 1.5%. Therefore, 15% is used as the preset coefficient of variation.

[0044] The target composite temperature is determined based on the coefficient of variation of the carbonyl absorption peak intensity and a preset coefficient of variation, and is used to regulate the curing uniformity of the two-component polyurethane adhesive.

[0045] As a preferred embodiment, under the condition that the chemical bonding structure is not stable, the composite temperature of the first composite substrate is adjusted by comparing the carbonyl absorption peak intensity difference with the preset intensity difference by comparing the carbonyl peak intensity variation coefficient with the preset intensity difference.

[0046] Specifically, if the carbonyl peak intensity difference is greater than or equal to a preset intensity difference, the composite temperature is increased by a first temperature adjustment coefficient to redetermine the target composite temperature. If the intensity difference of the carbonyl peak is less than the preset intensity difference, the recombination temperature is increased by the second temperature adjustment coefficient to redetermine the target recombination temperature.

[0047] In an optional embodiment of the present invention, the preset strength difference is set to 5%, the first temperature adjustment coefficient is set to 1.2, and the second temperature adjustment coefficient is set to 1.08. Thirty unqualified batches are sorted in ascending order of carbonyl peak intensity difference and grouped according to different preset strength difference values: 3%, 4%, 5%, 6%, and 7%. The performance improvement effect within each group is determined by increasing the composite temperature by a fixed margin of 10°C without adjusting other parameters. Statistical analysis shows that when the preset strength difference is 5%, if the carbonyl peak intensity difference is less than or equal to 5%, the peel strength retention rate can reach 82% after a 10°C increase, while if the carbonyl peak intensity difference is greater than 5%, it can only be increased to 62%. Therefore, 5% is used as the preset strength difference. Fifteen batches with carbonyl peak intensity differences between 2% and 4.9% and another 15 batches with carbonyl peak intensity differences between 6% and 10% were selected from historical production batches. For each group, different temperature adjustment coefficients were applied for heating. The coefficient of variation of carbonyl absorption peak intensity and the peel strength retention rate of the new batches after heating were determined. The minimum temperature adjustment coefficient corresponding to a carbonyl absorption peak intensity variation ≤ 15% and a retention rate ≥ 80% was used as the first and second temperature adjustment coefficients. The method for adjusting the composite temperature of the first composite substrate using the temperature adjustment coefficients is as follows: the product of the determined temperature adjustment coefficient and the original composite temperature is used to determine the target composite temperature. The target composite temperature should not exceed 90℃. If the target composite temperature exceeds 90℃, 90℃ is set as the target composite temperature.

[0048] Specifically, the PET reinforcing layer is a biaxially oriented polyester film with a thickness of 8μm to 12μm, and the surface is also corona treated with a surface tension of ≥50dyn / cm; the PET printing layer is a biaxially oriented polyester film with a thickness of 8μm to 12μm, and the non-composite side is corona treated to a surface tension of ≥42dyn / cm to facilitate subsequent printing. The composite side is not treated; the hybrid adhesive transition layer is an epoxy-polyurethane hybrid adhesive with the following formula by weight: 100 parts epoxy resin, 60-80 parts polyurethane prepolymer with 3%-5% NCO content, prepared from polyether glycol and TDI, 30-50 parts polyamide or modified amine curing agent, 1:1 diluent to adjust the solid content of the adhesive to 30%-40%, and 1-2 parts coupling agent KH-560; epoxy resin, polyurethane prepolymer, and coupling agent are added to the mixing tank in sequence, the diluent is added while stirring, and finally the curing agent is added. Stirring is continued for 15 minutes, and the mixture is allowed to stand for 10 minutes to remove bubbles before use.

[0049] Specifically, the metal barrier layer and the PET reinforcement layer of the first composite substrate are mounted face up on two unwinding shafts of a dry laminating machine. The unwinding tension is set to 80 N / m to 120 N / m for the first composite substrate and 60 N / m to 100 N / m for the PET reinforcement layer. An epoxy-polyurethane hybrid adhesive is uniformly coated onto the outer side of the metal barrier layer using an anilox roller coater, with a dry coating thickness of 1.0 μm to 2.5 μm. The coated substrate then enters a three-stage drying tunnel, with the temperature set at 60–70°C in the first stage and [temperature set at the second stage]. The temperature ranges from 70 to 80°C, with three sections at 80 to 90°C to ensure full solvent evaporation. The metal barrier layer coated with epoxy-polyurethane hybrid adhesive is bonded to the PET reinforcement layer between a heating roller and a pressure roller. The bonding temperature is 80°C to 100°C, the bonding pressure is 0.4 MPa to 0.7 MPa, and the bonding speed is 60 m / min to 100 m / min. After cooling and shaping by a cooling roller, the layers are wound up to form the second composite substrate. An epoxy-polyurethane hybrid transition layer with a thickness of 1.0 μm to 2.5 μm is formed between the metal barrier layer and the PET reinforcement layer.

[0050] Its layered structure, from the outside to the inside, is: PET reinforcement layer / hybrid adhesive transition layer / metal barrier layer / adhesive layer / CPP heat-sealing layer.

[0051] Specifically, the epoxy-polyurethane hybrid adhesive is formulated in the following proportions by weight: 100 parts epoxy resin; 60 to 80 parts of polyurethane prepolymer with an NCO content of 3% to 5% were prepared by reacting polyether glycol with TDI. 30 to 50 parts of curing agent, selected from either polyamide or modified amine; KH-560 1 to 2 servings; A mixed diluent prepared by mixing ethyl acetate and butanone in a volume ratio of 1:1 was used to adjust the solid content of the epoxy-polyurethane hybrid adhesive to 30%–40%.

[0052] The preparation method is as follows: add epoxy resin, polyurethane prepolymer and KH-560 into the mixing tank in sequence according to the ratio, slowly add the mixed diluent while stirring, and finally add the curing agent. Continue stirring for 15 minutes. After stirring, let it stand for 10 minutes to remove bubbles and set aside.

[0053] Specifically, the surface potential half-life of the second composite substrate is determined based on the surface potential decay curve of the PET reinforcement layer, and is used to characterize the crosslinking density and curing uniformity of the hybrid adhesive transition layer.

[0054] In a preferred embodiment, at least three square samples with dimensions of 100mm × 100mm are cut from the second composite substrate. A high-voltage electrostatic generator is used to generate a high-voltage electrostatic field with an electric field strength of 5kV / cm to 10kV / cm. The square samples are placed in the center of the high-voltage electrostatic field with an electrode spacing of 5cm to 8cm and charged for 30s to 60s. After charging, the surface potential of the central region of the PET reinforcement layer of the square sample is measured immediately using a probe electrometer or Kelvin probe, and the initial potential V0 is recorded. The surface potential is recorded every 10s for 2 minutes to obtain the surface potential decay curve of each sample over time. According to each surface potential decay curve, the time corresponding to the potential decreasing from V0 to 0.5V0 on the surface potential decay curve is determined as the surface potential half-life of a single sample. The arithmetic mean of the half-lives of all samples is taken as the surface potential half-life of the second composite substrate.

[0055] In this embodiment of the invention, during the crosslinking and curing process of the epoxy-polyurethane hybrid adhesive transition layer, the mobility of molecular chain segments decreases with increasing crosslinking density. After being charged by a high-voltage electrostatic field, charges are captured on the surface of the transition layer, and these charges leak through conductive or polarized pathways within the material. Higher crosslinking density results in tighter molecular chain binding, creating more charge traps, and consequently increasing the volume resistivity and surface resistivity of the material. This makes it difficult for injected charges to leak and migrate, resulting in slow surface potential decay and a longer half-life. Conversely, insufficient crosslinking allows for relatively free molecular chain movement, and charges easily leak rapidly through chain segment movement or impurity ion conduction, leading to rapid surface potential decay and a shorter half-life. Furthermore, the metal barrier layer is a good conductor, forming a complete electrostatic shielding layer during high-voltage electrostatic field detection. The applied electrostatic charge is only captured and stored by the intermediate hybrid adhesive transition layer. The two-component polyurethane adhesive layer and CPP heat-sealing layer on the side of the metal barrier layer are completely shielded and do not participate in the charge capture and decay process, thus preventing the introduction of additional charge traps or conduction paths. Therefore, the surface potential decay half-life can directly characterize the crosslinking quality of the transition layer of hybrid adhesives.

[0056] When cross-linking is sufficient, the hybrid adhesive transition layer forms a dense three-dimensional network, effectively preventing water, ethanol, and ions in the solution from penetrating to the metal surface. Simultaneously, the rigidity of the epoxy component and the toughness of the polyurethane component work together to resist interfacial shear stress between the metal barrier layer and the PET layer caused by heat sealing, filling, and drops. When cross-linking is insufficient, the molecular chains are mainly physically entangled, lacking sufficient chemical bonds, resulting in a loose network structure and the existence of microscopic free volume channels. This leads to a situation where, although the initial peel strength may meet the requirements, the insufficiently cross-linked molecular chains are easily plasticized and hydrolyzed after contact with the solution, causing a rapid decrease in adhesive strength and ultimately interfacial delamination. The solution can easily penetrate to the metal / adhesive layer interface, causing metal corrosion or adhesive layer swelling, forming a through-seepage path. Furthermore, the hybrid adhesive transition layer is too soft to effectively transfer and buffer stress, causing stress concentration at weak points in the interface and easily leading to crack propagation.

[0057] Please see Figure 3 As shown, it is a flowchart for determining whether the crosslinking quality of the hybrid adhesive transition layer is qualified according to an embodiment of the present invention.

[0058] In a preferred embodiment, if the surface potential half-life is greater than or equal to the preset half-life, the crosslinking quality of the hybrid adhesive transition layer is determined to be qualified. Based on the comparison result that the surface potential half-life is less than the preset half-life, it is determined that the crosslinking quality of the hybrid adhesive transition layer is unqualified.

[0059] In an optional embodiment of the present invention, the preset half-life is 120 s. At least 50 batches of the second composite substrate are taken, and the surface potential half-life is measured for each batch. The actual crosslinking degree of the hybrid adhesive transition layer and the peel strength retention rate of the composite film after immersion in a simulated drug solution are tested using the gel content method or DSC residual exothermic peak. When the surface potential half-life is ≥120 s, the crosslinking degree is >85%, and the peel strength retention rate is ≥80%; when the surface half-life is <120 s, the crosslinking degree is <70%, and the peel strength retention rate drops below 60%. Therefore, 120 s is used as the preset half-life.

[0060] The target curing time is determined based on the preset half-life and the surface potential half-life, and is used to regulate the crosslinking quality of the hybrid adhesive transition layer.

[0061] In a preferred embodiment, when the crosslinking quality of the hybrid adhesive transition layer is unqualified, the curing time of the composite film is adjusted to achieve the target curing time by comparing the half-life difference between the preset half-life and the surface potential half-life with the preset half-life difference.

[0062] Specifically, if the half-life difference is greater than or equal to the preset half-life difference, then the curing time of the composite membrane is increased by the first time adjustment coefficient to achieve the target curing time. If the half-life difference is less than the preset half-life difference, then the curing time of the composite membrane is increased by the second time adjustment coefficient to achieve the target curing time.

[0063] In an optional embodiment of the present invention, the preset half-life difference is set to 30 s, the first duration adjustment coefficient is set to 1.5, and the second duration adjustment coefficient is set to 1.2. At least 40 batches of second composite substrates with substandard crosslinking quality of the hybrid adhesive transition layer during historical preparation processes are obtained, covering a range from 1 s to 80 s. Samples are taken from each batch, and the half-life is tested at a fixed curing temperature of 50°C, with the curing time gradually extended from 24 hours to 72 hours. The minimum duration adjustment coefficient required to restore the surface potential half-life to 120 s is recorded. Statistical results show that when the preset half-life difference is less than or equal to 30 s, the minimum duration adjustment coefficient is 1.15; when the preset half-life difference is greater than 30 s, the minimum duration adjustment coefficient rises sharply to 1.48. Therefore, 30 s is used as the preset half-life difference to distinguish between mild and severe insufficiency in the crosslinking quality of the hybrid adhesive transition layer. Based on the predetermined half-life difference, the upper 75th percentile of the duration adjustment coefficient corresponding to mild insufficiency is taken as the first duration adjustment coefficient, and the upper 75th percentile of the duration adjustment coefficient corresponding to severe insufficiency is taken as the second duration adjustment coefficient.

[0064] In this embodiment of the invention, during the preparation of the composite film, curing involves placing the composite roll at a temperature of 40°C to 60°C, preferably 50°C, for a certain period of time. This allows the active groups in the adhesive, such as epoxy and isocyanate groups, to continue the crosslinking reaction with the curing agent, forming a three-dimensional network structure. For the epoxy-polyurethane hybrid system, after initial composite preparation: the adhesive has only completed the initial reaction, with approximately 30% to 50% crosslinking. The molecular chains are mainly connected by physical entanglement and a small number of chemical bonds, and the strength has not yet reached its peak. During the curing process, as time increases, the crosslinking reaction continues to advance, and the crosslinking density gradually increases, eventually reaching a stable value. When the surface potential decay half-life is too short, it indicates that the crosslinking density of the hybrid adhesive transition layer is lower than the target value, which may be due to insufficient curing time or too low curing temperature. Increasing the curing temperature may cause film shrinkage or degradation. Therefore, appropriately increasing the curing time provides more collision opportunities for the incompletely reacted active groups, promoting the crosslinking reaction to continue towards a higher conversion rate.

[0065] Specifically, the composite film preparation process is as follows: the PET reinforcing layer of the second composite substrate is unwound with the inner layer facing upwards and the PET printed layer is unwound with the inner layer facing downwards. The tension is set at 80 N / m to 120 N / m for the second composite substrate and 60 N / m to 90 N / m for the PET printed layer; a two-component polyurethane adhesive is used, with a dry coating amount of 1.5 g / m. 2 ~2.5g / m 2After drying, the layers are hot-pressed together at a lamination temperature of 70℃~85℃ and a lamination pressure of 0.4MPa~0.6MPa. After cooling by a cooling roller, the layers are wound up to obtain a composite film. The layered structure from the outside to the inside is: PET printing layer / adhesive layer / PET reinforcement layer / hybrid adhesive transition layer / metal barrier layer / adhesive layer / CPP heat-sealing layer.

[0066] In the embodiments of this invention, the adhesive layer is a two-component polyurethane adhesive.

[0067] In a preferred embodiment, the formulation of the leakage detection simulation solution is as follows: 0.1 g of Rhodamine B is added to every 1000 ml of simulation solution. The composite film is filled with the leakage detection simulation solution using a strip packaging machine at a rate of 150 packs / min, a heat-sealing temperature of 140°C, a heat-sealing pressure of 0.3 MPa, and a heat-sealing time of 0.3 s, yielding several strips. The filled strips are then immersed in water and vacuum-pressurized at -0.08 MPa for 2 minutes.

[0068] Specifically, the heat-sealed strip package was irradiated with a 365nm ultraviolet lamp and a fluorescence microscope was used to obtain fluorescence images of the heat-sealed area.

[0069] In this embodiment of the invention, the fluorescent leakage area is determined based on the fluorescent leakage points in the fluorescent image.

[0070] In a preferred embodiment, the fluorescence image is converted into an 8-bit grayscale image and preprocessed such as denoising and filtering. Pixels in the preprocessed fluorescence image with a grayscale greater than a preset grayscale are identified as fluorescence leakage points. The area of ​​connected fluorescent leakage points is defined as the fluorescent leakage region.

[0071] In an optional embodiment of the present invention, the preset grayscale is three times the average grayscale of the background of the fluorescent image.

[0072] In this embodiment of the invention, the fluorescent leakage area feature includes leakage area ratio and leakage path width, wherein the leakage area ratio is the percentage of the pixel area of ​​the fluorescent leakage area to the total area of ​​the heat-sealed area. The leakage path width is the maximum width value in the normal direction along the extension direction of the leakage path in the fluorescent leakage area.

[0073] In a preferred embodiment, for linear or strip-shaped fluorescent leakage areas, the central axis of the fluorescent leakage area is extracted using image analysis software. The maximum value of the local width of each pixel perpendicular to the central axis is taken as the leakage path width. If the leakage area is dot-shaped or irregular, the leakage path width is the major axis length or Freret diameter of the equivalent ellipse of the fluorescent leakage area, which can be automatically calculated using image analysis software such as ImageJ. This is existing technology and will not be elaborated further. It is understood that the larger the leakage area ratio and the larger the leakage path width, the worse the sealing of the strip package and the greater the probability of drug leakage.

[0074] Please see Figure 4 As shown, it is a flowchart for determining the sealing performance of the strip package according to an embodiment of the present invention.

[0075] In this embodiment of the invention, the sealing performance of the strip package is determined based on the leakage area ratio and the leakage path width. If the leakage area ratio is greater than the preset area ratio, or the leakage path width is greater than the preset width, then the sealing performance of the strip package is determined to be unqualified. If the percentage of the leakage area is less than or equal to the preset percentage of the area, and the width of the leakage path is less than or equal to the preset width, then the sealing performance of the strip package is determined to be qualified.

[0076] In an optional embodiment of this invention, the preset area percentage is 0.5%, and the preset width is 20 μm. By retrieving the leakage area percentages of at least 50 historical qualified batches and 40 historical abnormal leakage batches, it was found that when the leakage area percentage in historical batches was ≤0.5%, the average leakage rate after long-term immersion in the medicine was ≤0.2%, and the heat seal strength retention rate was ≥85%, fully meeting the compliance requirements for pharmaceutical strip packaging sealing. When the leakage area percentage was >0.5%, the leakage rate increased sharply to over 1.2%, and the heat seal interface was prone to gradual microporous penetration and localized micro-delamination. Therefore, the preset area percentage was determined to be 0.5%. For 90 historical batches of fluorescent dye leakage areas, the leakage path width was uniformly calculated using the Ferrette diameter. Statistical analysis revealed that when the leakage path width was ≤20μm, the leakage area consisted only of discontinuous, isolated micropores, unable to form a continuous capillary channel. Ethanol and surfactants in the solution could not continuously penetrate along the interface, and no long-term leakage failure cases were observed. When the leakage path width was >20μm, a continuous, continuous leakage channel formed in the heat-sealed area, and later, plasticization of the adhesive layer, micro-peeling of the interface, and obvious leakage were commonly observed. Therefore, a preset width of 20μm was determined.

[0077] In this embodiment of the invention, silica is a commonly used anti-adhesion filler in CPP heat-sealing layers. When the addition amount is too high, the hard particles easily lead to an increase in micropores in the matrix and hinder the heat-sealing fusion of resin molecular chains, forming leakage channels and causing sealing failure. Reducing its mass fraction can decrease the destructive effect of inorganic particles on the heat-sealing interface, promote the full melting and entanglement of CPP resin, construct a dense and continuous heat-sealing layer, effectively eliminate microscopic leakage defects, and improve the sealing performance of the strip package.

[0078] Specifically, when the package seal is not up to standard, the mass fraction of silica in the CPP heat-sealing layer is reduced until the package seal is up to standard. The mass fraction of silica corresponding to the package seal being up to standard is the target mass fraction of silica.

[0079] The pharmaceutical liquid strip packaging composite film of this invention includes, from the outside to the inside: a PET printing layer, an adhesive layer, a PET reinforcing layer, a hybrid adhesive transition layer, a metal barrier layer, an adhesive layer, and a CPP heat-sealing layer treated with corona discharge.

[0080] Example 1

[0081] raw material: The CPP heat-sealing layer is corona treated to a surface tension ≥42 dyn / cm; the metal barrier layer is a 6μm thick aluminum foil, with a 0.3μm thick KH-550 silane coupling agent primer coating on the composite side; the PET reinforcement layer is a 10μm thick biaxially oriented polyester film, with a surface tension ≥50 dyn / cm after corona treatment; the PET printing layer is a 10μm thick biaxially oriented polyester film, with a surface tension ≥42 dyn / cm on the non-composite side after corona treatment.

[0082] Two-component polyurethane adhesive: The main component is a hydroxyl component, comprising 100 parts by weight of saturated polyester polyol, 40 parts by weight of ethyl acetate, 8 parts by weight of anhydrous ethanol, 0.5 parts by weight of hydrolysis stabilizer, and 0.2 parts by weight of wetting and leveling agent, with a hydroxyl value of 60 mg KOH / g, a solid content of 55%, and a viscosity of 2000 mPa·s at 25℃; the curing agent is an isocyanate component, comprising 100 parts by weight of IPDI trimer isocyanate and 45 parts by weight of ethyl acetate, with an NCO mass fraction of 18, a solid content of 60%, and a viscosity of 1000 mPa·s at 25℃; the on-site mixing ratio is main component: curing agent = 100:22, diluted with ethyl acetate to a working solid content of 32%.

[0083] Epoxy-polyurethane hybrid adhesive: by weight, it comprises 100 parts epoxy resin, 70 parts polyurethane prepolymer with 4% NCO content obtained by polyether glycol and TDI, 40 parts polyamide curing agent, and 1.5 parts KH-560 coupling agent; the mixed diluent is ethyl acetate:butanone = 1:1, and the amount added is 100% of the total solid mass, adjusting the solid content to 35%; the epoxy resin, polyurethane prepolymer, and KH-560 are mixed in sequence, the diluent is added, and finally the curing agent is added, stirred for 15 minutes, and allowed to stand for 10 minutes to degas before use.

[0084] Preparation process: Preparation of the first composite substrate: The first composite substrate was prepared using an initial composite temperature of 75℃, a composite pressure of 0.5MPa, and a composite speed of 80m / min. The first composite substrate sample was immersed in a simulated drug solution at 40℃ for 72h. The carbonyl absorption peak intensity variation coefficient detected by micro-infrared spectroscopy was 18%, which is greater than the preset variation coefficient of 15%, indicating that the chemical bonding structure stability is unqualified. The calculated variation coefficient difference was 3%, which is less than the preset intensity difference of 5%. A second temperature adjustment coefficient of 1.08 was used, and the adjusted composite temperature was 75℃×1.08=81℃. The composite was re-composite at the adjusted temperature, and the carbonyl absorption peak intensity variation coefficient was re-measured. The chemical bonding structure stability was qualified.

[0085] Preparation of the second composite substrate: The first composite substrate is composited with a PET reinforcing layer, and the dry base thickness of the epoxy-polyurethane hybrid adhesive transition layer is 1.5 μm. After high voltage electrostatic field testing, the surface potential half-life is 130s, which is greater than the preset half-life of 120s. The crosslinking quality of the hybrid adhesive transition layer is qualified, and there is no need to adjust the curing time of the composite film.

[0086] Preparation of finished composite film: The second composite substrate is laminated with the PET printing layer and cured at 50°C for 48 hours; after simulated filling and fluorescence detection, the leakage area ratio is 0.3% and the leakage path width is 15μm, which meets the sealing requirements.

[0087] Example 2

[0088] raw material: The raw material composition is completely consistent with that of Example 1.

[0089] Preparation process: Preparation of the first composite substrate: The first composite substrate was prepared at a composite temperature of 80℃, a composite pressure of 0.6MPa, and a composite speed of 90m / min. The coefficient of variation of the carbonyl absorption peak intensity was tested and found to be 13%, which is less than the preset coefficient of variation of 15%, indicating that the chemical bonding structure is stable.

[0090] Preparation of the second composite substrate: The surface potential half-life of the second composite substrate was detected by a high-voltage electrostatic field and found to be 90s, which is less than the preset half-life of 120s, indicating that the crosslinking quality of the hybrid adhesive transition layer is unqualified; the calculated half-life difference is 30s, which is equal to the preset half-life difference of 30s. Using the first time length adjustment coefficient of 1.5, the curing time after adjustment is 24h×1.5=36h; the surface potential half-life was retested and found to be 125s, indicating that the crosslinking quality is qualified.

[0091] Preparation of finished composite film: The initial CPP heat-sealing layer contained 0.15% silica by mass. Simulated filling fluorescence detection showed a leakage area of ​​0.8% and a leakage path width of 25μm, indicating that the strip package seal was unqualified. The silica by mass fraction in the initial CPP heat-sealing layer was reduced to the target mass fractions of 0.14%, 0.13%, 0.12%, and 0.11%, respectively. The leakage area and leakage path width were retested, and it was found that the strip package seal was qualified when the target mass fraction was 0.12%.

[0092] Comparative Example 1 raw material: The raw material composition is completely consistent with that of Example 1.

[0093] Preparation process: First, a first composite substrate is prepared at a composite temperature of 70℃, a composite pressure of 0.5MPa, and a composite speed of 80m / min. Then, the first composite substrate is laminated with a PET reinforcing layer to obtain a second composite substrate. Finally, the second composite substrate is laminated with a PET printing layer to obtain the finished composite film.

[0094] The composite membranes prepared in Examples 1 and 2 and Comparative Example 1 were sampled and tested. The test results are shown in Table 1.

[0095] Table 1 Performance Test Results

[0096] As shown in Table 1, the average batch leakage rate of the pharmaceutical liquid strip packaging composite film prepared in this embodiment is less than 0.2%, which effectively solves the problems of unstable interlayer adhesion, insufficient cross-linking, and poor heat sealing of existing pharmaceutical composite films, and significantly improves the composite film's resistance to drug erosion and long-term storage stability.

[0097] The technical solution of the present invention has been described above with reference to the preferred embodiments shown in the accompanying drawings. However, it will be readily understood by those skilled in the art that the scope of protection of the present invention is obviously not limited to these specific embodiments. Without departing from the principles of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will all fall within the scope of protection of the present invention.

Claims

1. A process for the preparation of a pharmaceutical liquid strip-pack composite film, characterized in that, include: A first composite substrate is formed by bonding a corona-treated CPP heat-sealing layer and a metal barrier layer with an adhesive. The first composite substrate is then immersed in a simulated drug solution. On the composite side of the metal barrier layer, i.e. the side opposite to the CPP heat-sealing layer, a layer of silane coupling agent primer is pre-coated between the surface of the metal barrier layer and the adhesive layer to enhance the chemical bonding between the metal surface and the adhesive, thereby improving the long-term stability against drug immersion. The adhesive is a two-component polyurethane adhesive. The stability of the chemical bonding structure is determined based on the coefficient of variation of the carbonyl absorption peak intensity of the adhesive layer of the first composite substrate, and the target composite temperature of the first composite substrate is re-determined. The coefficient of variation of the carbonyl absorption peak intensity is determined based on the carbonyl peak area in a preset wavelength range in the infrared spectrum, and is used to characterize the degree of curing crosslinking and the uniformity of distribution of the two-component polyurethane adhesive. The metal barrier layer and the PET reinforcement layer are bonded together using an epoxy-polyurethane hybrid adhesive to form a second composite substrate, wherein the epoxy-polyurethane hybrid adhesive is formulated in the following proportions by weight: 100 parts epoxy resin; 60 to 80 parts of polyurethane prepolymer with an NCO content of 3% to 5% were prepared by reacting polyether glycol with TDI. 30 to 50 parts of curing agent, selected from either polyamide or modified amine; KH-560 1 to 2 servings; A mixed diluent prepared by mixing ethyl acetate and butanone at a volume ratio of 1:1 was used to adjust the solid content of the epoxy-polyurethane hybrid adhesive to 30%–40%. The crosslinking quality of the hybrid adhesive transition layer is determined based on the surface potential half-life of the second composite substrate treated with a high-voltage electrostatic field, and the target curing time of the composite film is determined. The PET reinforcement layer of the second composite substrate is laminated with the PET printing layer to form a composite film; The sealing performance of the strip package was determined based on the fluorescent leakage area characteristics of the heat-sealed area of ​​the composite film after simulated filling, and the target mass fraction of silica in the CPP heat-sealing layer was determined. The chemical bonding structure is not stable enough, which is determined based on the fact that the coefficient of variation of the carbonyl absorption peak intensity is greater than the preset coefficient of variation. The target composite temperature is determined based on the coefficient of variation of the carbonyl absorption peak intensity and a preset coefficient of variation, and is used to regulate the curing uniformity of the two-component polyurethane adhesive. The crosslinking quality of the hybrid adhesive transition layer is unqualified, which is determined based on the fact that the surface potential half-life is less than the preset half-life. The surface potential half-life is determined based on the surface potential decay curve of the PET reinforcement layer, and is used to characterize the crosslinking density and curing uniformity of the hybrid adhesive transition layer. The target curing time is determined based on the preset half-life and the surface potential half-life, and is used to regulate the crosslinking quality of the hybrid adhesive transition layer.

2. The method for preparing the pharmaceutical liquid strip packaging composite film according to claim 1, characterized in that, The fluorescent leakage area characteristics include the leakage area percentage and the leakage path width, wherein, The percentage of the leakage area is the percentage of the pixel area of ​​the fluorescent leakage area to the total area of ​​the heat-sealed area. The leakage path width is the maximum width value in the normal direction along the extension direction of the leakage path in the fluorescent leakage area.

3. The method for preparing the pharmaceutical liquid strip packaging composite film according to claim 2, characterized in that, The failure of the strip package to meet the sealing requirements is determined based on the fact that the leakage area ratio is greater than the preset area ratio, or the leakage path width is greater than the preset width.

4. A composite film for pharmaceutical liquid strip packaging, characterized in that, The preparation method of the pharmaceutical liquid strip packaging composite film according to any one of claims 1-3 comprises, from the outside to the inside: a PET printing layer, a two-component polyurethane adhesive layer, a PET reinforcing layer, an epoxy-polyurethane hybrid adhesive transition layer, a metal barrier layer, a two-component polyurethane adhesive layer, and a CPP heat-sealing layer treated with corona discharge.

Images