Film analysis: No stone unturned

Jo Smewing explores new methods to help pharmaceutical manufacturers quantify and analyse the performance characteristics of pharmaceutical film applications

Developments in the field of both oral and transdermal drug delivery methods are paving the way to the future of systemic drug administration. Films have long been recognised as ideal carriers for products that require ultra-high barrier properties in a transparent, small footprint package for pharmaceutical and nutraceutical applications. But with the advent of Controlled Release (CR) pharmaceutical dosage forms that release active ingredients gradually and predictably, films are increasingly finding their way into new drug applications. For an effective clinical performance films must adhere reliably to the target organ and withstand daily wear without compromising their functionality.

Automated texture analysis allows CR films to be tested in objectively controlled conditions that closely simulate real applications. TA provides a rapid and simple technique for measuring the adhesiveness, rupture, burst strength, resilience and relaxation properties of pharmaceutical films.

Transdermal CR films usually combine a therapeutic component with an adhesive formulation that ensures a continuous delivery of the active ingredient through unbroken skin at a constant absorption rate. Skin adhesion and drug compatibility determine the efficacy of transdermal applications.  Adhesive properties are critical because the amount of medication delivered is directly proportional to the skin contact area. Transdermal systems need to cause minimum skin disruption, be easy to handle and be equally effective for the infinite variations in human skin. In vitro tests are commonly used to determine and compare tack, peel adhesion, tensile and shear characteristics of film samples.
Polymeric films are typical examples of dermal delivery drugs. Their retention on the affected area is challenged by various shearing forces such as breathing, swallowing and flexing of the skin. Their performance depends on bioadhesion and good drug release.

Adhesive film patches are widely used in highly targeted and custom-designed applications. Bioadhesive polymer composition is combined with the moisture-activated drug release system to provide effective localised treatment that is simple to produce and easy to use. The efficacy of topical films is dependent on correct application to the skin and the retention of the product on the body for a sustained period. Incorrect application can result in inconsistent results from the same medication, so new moisture-activated patch applications have been developed to overcome these issues. In contrast to topical creams, the fixed dimensions of transdermal patches ensure better coverage of the affected area and control the release of active ingredients as well as their retention. Clinically relevant product groups include hydrocolloids and hydropolymers, semipermeable films, gelatine films and calcium alginates.

In a test to measure the bioadhesion of topical films, an adhesive sample is attached to a cylinder probe, which is then lowered onto a neonate porcine skin sample (which closely resembles the human epidermis). The texture analyser - in this case a TA.XTplus - then measures the force required to remove the probe from the skin surface. To tailor the test conditions to the specific requirements of hydrogel films, a flexible substrate clamp can be used to secure both the sample and the skin in place. The device consists of a multi-slot plate and a clamp fixture and works in conjunction with an adhesive indexing system. The skin sample is held under the plate and the upper fixture lowers the sample down into each slot. The texture analyser then records the force required to withdraw after adhesive bonds have been formed.

To assess the peel strength of a typical bi-laminar patch formulation, a cyanoacrylate adhesive is used to attach wetted neonate porcine skin to the sliding platform of a 90 degree peel rig. A sample of the patch is secured vertically; held at the top with a clamp, and at the bottom attached to the skin. As the clamp moves upwards, the sliding section of the rig moves horizontally, forming a 90 degree angle between the interface of the skin sample and the adhesive patch. A texture analyser records the force required to peel the patch off the skin sample.

Oral delivery accounts for 90% of all medicines prescribed. However, degradation of the drug by the stomach's enzymes and acids, as well as liver metabolism and absorption challenge the efficacy of many oral dosage forms. New developments taking place in this area include delivering medication through fast-dissolving tablets and films designed to manipulate biological barriers and deliver required absorption rates.

Film tablet coatings are popular because of their multiple roles: from aesthetics and masking taste and odour to eased ingestion and prolonged product shelf life. Problematically, aqueous film coatings tend to act as local stress concentrators, promoting cracking, edge splitting and peeling. To assess these risks accurately, Stable Micro Systems developed the Tablet Coating Adhesion Fixture, which calculates the force required to separate a tablet from its coating. The coating is removed from around the circumference of the tablet using a scalpel, leaving it present only on the upper and lower surfaces. Lower and upper fixture cavities are covered with double-sided foam tape, and the prepared tablet is then positioned in the lower cavity. As the test starts, the upper fixture descends onto the tablet at a specific force for a defined time. Once the sample has been fully compressed into both cavities, ensuring full coating contact with the adhesive, the upper fixture is withdrawn, either removing the upper coating or leaving the lower one in the stationary fixture. The maximum force required to separate the tablet from its coating is known as the “tablet coating adhesion force.”

Mucosal delivery requires a drug delivery system to be attached to a target area of mucous membrane, such as a part of the gut, for a predefined length of time. Its success depends on the strength of the product’s mucoadhesive bonds, which can be measured using the TA.XTplus. Simple adhesive tests, similar to the ones described above, provide details of the mucoadhesive properties of films, powders, gastrospheres or polymers. Developed by Stable Micro Systems and the University of Strathclyde, the Mucoadhesion Rig, closely replicates in vivo conditions with a porcine membrane sample positioned in a fixed volume of temperature-regulated gastric fluid. A cylinder probe, with sample attached, descends into the vessel until the sample is in contact with the tissue. The texture analyser controls the force and time of contact between the two surfaces and records the force required to separate the surfaces, thereby measuring the mucoadhesion strength.

The application of polymeric films depends on their mechanical, electrical, thermal and bonding properties. These may be assessed by using tensile, shear and compression techniques. Subjecting films to tensile stress is widely used as a fast and accurate method of defining whether the material is strong and flexible enough for transdermal pharmaceutical applications. Tensile grips allow manufacturers to optimise the balance between drug loading and plasticiser content to ensure the required clinical performance. Attached to the base plate and the cross head of the Texture Analyser, tensile grips firmly hold the film sample from both ends. A test is then performed at a predetermined speed and the results, such as tensile strength, work of failure, elastic modulus and extension, or elongation to break, are calculated from load-extension curves. Pneumatic grips are often a preferred means of holding a sample for tensile testing because the gripping pressure can be controlled precisely as it is not affected by the deformation of the sample.

Although tensile or pneumatic grips are traditionally used to assess the tensile properties of polymeric films, the reproducibility of results can be compromised if the pressure is unevenly distributed across the sample’s surface area. By comparison, the film support rig can hold small sections of film in a drum configuration, which means the pressure is evenly distributed around the circumference of the sample. A puncture test performed by a spherical probe determines the film’s burst strength as well as resilience, stiffness and relaxation.

Pharmaceutical films are becoming increasingly prevalent among OTC pharmaceutical products, ranging from tablet coatings to fast-dissolving film wafers and transdermal patches. Because of their optimal physical structure, films are discreet, have good adhesion and peel profiles and do not interfere with daily activities. Facilitating repeatable and reliable testing of various mechanical properties of film applications, texture analysis enables pharmaceutical manufacturers to evaluate and evolve their products. Extensive tests help to identify optimal material and drug dosage formulations that promote stability and long-term performance of a product.

Author: Jo Smewing is applications manager at Stable Micro Systems

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