Formulating active pharmaceutical ingredients (APIs) often presents significant challenges, such as instability, low solubility, low permeability and potential safety concerns. The properties of softgel products, including their oil-based nature to improve drug absorption and sealed environment to reduce dust and operator exposure, help to overcome these issues. Softgel capsules are highly versatile, capable of encapsulating a wide range of APIs in various forms, including solutions, suspensions, and semi-solids. They have played a crucial role in the success of many drugs by addressing stability and shelf-life challenges, while offering significant advantages that enhance drug delivery and patient compliance.
Chris Cuthbertson, Program Manager of Pharmaceutical Development at Douglas CDMO, explores the technical aspects of softgel formulations and explains why their unique characteristics make them a preferred dosage form for manufacturers and patients alike.
Softgel capsules are typically comprised of a gelatinous outer shell, but alternative non-animal/plant-based shell materials can also be used. This outer shell encases a liquid, or semi-liquid fill that is often oil based. This oil-based fill is an excellent carrier, as APIs dissolved or suspended in an oil matrix are more readily absorbed in target areas of the body through controlled release.
Chris discusses the technical methods employed at Douglas CDMO to enhance the solubility of softgel products, noting that several techniques are used depending on the drug’s specific requirements. “We utilize lipid-based systems to enhance the solubility of poorly water-soluble drugs,” explains Chris, referring to self-emulsifying drug formulations that, when ingested, form emulsions, or microemulsions, which can enhance the drug’s solubility and improve absorption into the bloodstream.
Douglas CDMO also employs permeation enhancers and particle-size reduction. “Incorporating surfactants or fatty acids into our formulations enhances a drug’s permeability across biologic membranes, leading to improved absorption.” Chris highlights that smaller particle size drug substances have a greater surface area, facilitating faster dissolution. “By tailoring particle sizes for each drug, it may be possible to significantly improve bioavailability and overall performance.”
Collectively, these techniques increase absorption and overall bioavailability, helping to ensure that the lowest effective drug dose is used to achieve full therapeutic effect. This reduces pill burden and minimizes the risk of side effects and enables APIs to be more readily absorbed in the body.
The softgel casing needs to be durable and often contains pigments and opacity agents to protect the API from light and oxygen, thereby enhancing stability and extending shelf life. Additionally, an enteric gelatin can be used to protect the shell from the stomach’s acidic environment, allowing the capsule to reach the more neutral environment of the small intestine, where it can then rapidly release its contents.
Light, oxygen, and moisture can significantly impact the stability of APIs in softgel formulations. For example, exposure to light can cause degradation through photochemical reactions. Chris notes that dispensing light-sensitive drugs under low actinic light helps mitigate this issue. “Essentially, it’s yellow light, and unlike fluorescent or daylight, it won’t degrade your compound. Douglas has a lot of experience handling oxygen and light-sensitive molecules.”
Inert atmospheres are used to handle compounds sensitive to oxidation. “By utilizing oxygen-free environments during the dispensing process, once the drug is combined with the oil-based fill, we create a protective environment that shields the API from oxidative damage,” explains Chris. This also ensures the fill is moisture free, providing protection for APIs sensitive to moisture.
The choice of excipient helps maintain the stability of softgel formulations. “If a drug is susceptible to oxidation, we can add an antioxidant such as butylated hydroxytoluene to help prevent degradation,” says Chris. Being aware of possible excipient interactions, especially with the outer gelatin shell, is also important. Chris explains some excipients can cause cross-linking to occur within the gelatin shell, reducing the solubility of the capsule. “Choosing the gelatin grade and knowing the excipients to avoid is important for a successful formulation.”
Photo: Douglas CDMO
Compatibility testing is part of this initial process, where excipients are selected based on their interactions with the API, followed by small-scale lab-batch prototyping. “Every stage of the development is approached with a ‘quality-by-design’ mindset,” says Chris. “We conduct risk assessments and experimental trials to identify potential issues early on, ensuring the formulation meets quality standards and performance criteria.”
The proprietary intellectual property is often associated with the liquid fill inside the capsule. The complex nature of softgel manufacturing, involving specialized equipment and proprietary formulations, presents significant barriers to their generic production. This complexity ensures the preservation of product quality and efficacy, safeguarding investments.
Douglas CDMO addresses complex requirements through flexible processes, innovative technologies, and collaborative client partnerships. Chris highlights that customization is integral to Douglas’s approach. “We adjust the capsule fill to meet exact dosage needs and target specific release profiles. We also customize the capsule shell, including size, shape, color, and imprinting, to ensure ease of use and that our client has a visually appealing product.”
Douglas CDMO manages the manufacturing process for their softgel formulations with a strong focus on preparation. Early collaboration between formulation scientists and process engineers ensures a smooth transition from laboratory to commercial manufacture, enabling quality and consistency. “Early preparation is key to a smooth manufacturing process,” reiterates Chris. “We use a systematic approach to scaling up production and commercialization, ensuring our softgel formulations maintain their quality and consistency, from pilot batches to full-scale production.”
Extensive pilot studies help optimize formulations by evaluating various excipients, processing parameters, and encapsulation techniques. Douglas CDMO employs stringent quality-control measures, including in-process testing and comprehensive final-product testing, so that batches maintain integrity and adherence to predefined standards and regulatory compliance is ensured.
Chris also attributes Douglas CDMO’s product quality to its advanced facilities and skilled personnel.
“We employ state-of-the-art machinery that ensures precise dosing and consistent product quality, supported by experienced production operators who have been formulating softgel capsules at Douglas for many years,” he explains.
Chris acknowledges that the higher production costs for softgels compared to tablets can be a deterrent when selecting it as a dosage form.
“It is often perceived that softgel capsules are more expensive to produce than tablets. What this doesn’t consider is that your API may be more bioavailable in the softgel dosage form. If the API is expensive, the cost of conversion is more than compensated for by the savings in drug substance input cost.”
Chris highlights the strengths Douglas offers as a CDMO partner, noting, “Few pharmaceutical companies can consistently deliver high-quality softgel capsules, leading many to exit the market due to quality issues. However, we’ve managed to maintain our market share in both the US and Europe, thanks to the superior quality of our products and the expertise of our team.” He credits the company’s technical expertise, technological capabilities, and stringent quality control processes as central to its success.
Quality is paramount in the production of softgel formulations and is a crucial consideration for companies seeking to engage a CDMO partner. Chris emphasizes, “Our team’s vigilance in all areas of production – from development to manufacturing to market quality surveillance, whether for novel or generic drug production – provides a significant advantage for our clients.” He further explains that Douglas’s strict adherence to quality control protocols, including cleaning, cross-contamination validation, and safety procedures for handling toxic compounds, makes the company a highly competitive CDMO partner.
Douglas CDMO can engage with companies at various stages of drug development, from early formulation to later stages in a product’s life cycle. For both novel and generic compounds, Chris advises companies to involve Douglas CDMO early in the formulation development process to ensure the most bioavailable and stable formulation is used in clinical studies. “We have extensive experience with early-stage product development. We can support our clients through first-in-human trials, registrational studies, and guide them in the supply of commercial products,” he concludes.
Learn more at www.douglascdmo.com
Chris Cuthbertson, Program Manager of Pharmaceutical Development at Douglas CDMO, explores the technical aspects of softgel formulations and explains why their unique characteristics make them a preferred dosage form for manufacturers and patients alike.
Bioavailability enhancement
The primary advantage of softgel capsules is their ability to increase the bioavailability of poorly soluble drugs. This makes them an especially attractive option for formulators when the API has limited solubility and absorption in the gastrointestinal (GI) tract, requiring enhanced delivery mechanisms to achieve therapeutic effectiveness. The inside fill of the capsules can be precisely formulated with solubilizers and emulsifiers to enhance the dissolution and absorption of the API in the GI tract.Softgel capsules are typically comprised of a gelatinous outer shell, but alternative non-animal/plant-based shell materials can also be used. This outer shell encases a liquid, or semi-liquid fill that is often oil based. This oil-based fill is an excellent carrier, as APIs dissolved or suspended in an oil matrix are more readily absorbed in target areas of the body through controlled release.
Chris discusses the technical methods employed at Douglas CDMO to enhance the solubility of softgel products, noting that several techniques are used depending on the drug’s specific requirements. “We utilize lipid-based systems to enhance the solubility of poorly water-soluble drugs,” explains Chris, referring to self-emulsifying drug formulations that, when ingested, form emulsions, or microemulsions, which can enhance the drug’s solubility and improve absorption into the bloodstream.
Douglas CDMO also employs permeation enhancers and particle-size reduction. “Incorporating surfactants or fatty acids into our formulations enhances a drug’s permeability across biologic membranes, leading to improved absorption.” Chris highlights that smaller particle size drug substances have a greater surface area, facilitating faster dissolution. “By tailoring particle sizes for each drug, it may be possible to significantly improve bioavailability and overall performance.”
Collectively, these techniques increase absorption and overall bioavailability, helping to ensure that the lowest effective drug dose is used to achieve full therapeutic effect. This reduces pill burden and minimizes the risk of side effects and enables APIs to be more readily absorbed in the body.
Stability and protection
Preserving the potency and efficacy of the API over time is crucial for regulatory compliance and safety reasons. A stable formulation prevents harmful degradation, ensuring the medication remains safe and effective until its expiration date. This reliability also enhances consumer confidence and trust in the product. Softgel capsules offer enhanced stability for active ingredients sensitive to air, moisture, or light.The softgel casing needs to be durable and often contains pigments and opacity agents to protect the API from light and oxygen, thereby enhancing stability and extending shelf life. Additionally, an enteric gelatin can be used to protect the shell from the stomach’s acidic environment, allowing the capsule to reach the more neutral environment of the small intestine, where it can then rapidly release its contents.
Light, oxygen, and moisture can significantly impact the stability of APIs in softgel formulations. For example, exposure to light can cause degradation through photochemical reactions. Chris notes that dispensing light-sensitive drugs under low actinic light helps mitigate this issue. “Essentially, it’s yellow light, and unlike fluorescent or daylight, it won’t degrade your compound. Douglas has a lot of experience handling oxygen and light-sensitive molecules.”
Inert atmospheres are used to handle compounds sensitive to oxidation. “By utilizing oxygen-free environments during the dispensing process, once the drug is combined with the oil-based fill, we create a protective environment that shields the API from oxidative damage,” explains Chris. This also ensures the fill is moisture free, providing protection for APIs sensitive to moisture.
The choice of excipient helps maintain the stability of softgel formulations. “If a drug is susceptible to oxidation, we can add an antioxidant such as butylated hydroxytoluene to help prevent degradation,” says Chris. Being aware of possible excipient interactions, especially with the outer gelatin shell, is also important. Chris explains some excipients can cause cross-linking to occur within the gelatin shell, reducing the solubility of the capsule. “Choosing the gelatin grade and knowing the excipients to avoid is important for a successful formulation.”
Photo: Douglas CDMO
Customization and flexibility
When Douglas CDMO is approached for a project, the first task is a detailed discussion to understand the client’s specific needs, goals, and challenges. “The more information we gather, the smoother and faster the development process is,” explains Chris. “We define the desired ‘profile’ or the characteristics of the API required to treat a particular disease state.” Chris adds, “Once we understand what a client needs, we can tailor a formulation based on the API’s unique properties. This is where understanding the sensitivity of your API is critical.”Compatibility testing is part of this initial process, where excipients are selected based on their interactions with the API, followed by small-scale lab-batch prototyping. “Every stage of the development is approached with a ‘quality-by-design’ mindset,” says Chris. “We conduct risk assessments and experimental trials to identify potential issues early on, ensuring the formulation meets quality standards and performance criteria.”
The proprietary intellectual property is often associated with the liquid fill inside the capsule. The complex nature of softgel manufacturing, involving specialized equipment and proprietary formulations, presents significant barriers to their generic production. This complexity ensures the preservation of product quality and efficacy, safeguarding investments.
Douglas CDMO addresses complex requirements through flexible processes, innovative technologies, and collaborative client partnerships. Chris highlights that customization is integral to Douglas’s approach. “We adjust the capsule fill to meet exact dosage needs and target specific release profiles. We also customize the capsule shell, including size, shape, color, and imprinting, to ensure ease of use and that our client has a visually appealing product.”
Manufacturing considerations
The potential toxicity of a drug substance should be carefully considered when deciding on a dosage form. Softgel manufacturing offers a safer environment for employees, especially when compared to the dust potential associated with tablet production.Douglas CDMO manages the manufacturing process for their softgel formulations with a strong focus on preparation. Early collaboration between formulation scientists and process engineers ensures a smooth transition from laboratory to commercial manufacture, enabling quality and consistency. “Early preparation is key to a smooth manufacturing process,” reiterates Chris. “We use a systematic approach to scaling up production and commercialization, ensuring our softgel formulations maintain their quality and consistency, from pilot batches to full-scale production.”
Extensive pilot studies help optimize formulations by evaluating various excipients, processing parameters, and encapsulation techniques. Douglas CDMO employs stringent quality-control measures, including in-process testing and comprehensive final-product testing, so that batches maintain integrity and adherence to predefined standards and regulatory compliance is ensured.
Chris also attributes Douglas CDMO’s product quality to its advanced facilities and skilled personnel.
“We employ state-of-the-art machinery that ensures precise dosing and consistent product quality, supported by experienced production operators who have been formulating softgel capsules at Douglas for many years,” he explains.
Chris acknowledges that the higher production costs for softgels compared to tablets can be a deterrent when selecting it as a dosage form.
“It is often perceived that softgel capsules are more expensive to produce than tablets. What this doesn’t consider is that your API may be more bioavailable in the softgel dosage form. If the API is expensive, the cost of conversion is more than compensated for by the savings in drug substance input cost.”
Douglas CDMO: delivering world-class expertise in softgel technology
Recognized for their specialization in high-potency softgel formulations, New Zealand-based Douglas is a key supplier of pharmaceutical softgels to both the US and European markets. Leveraging advanced technology and research expertise, the company develops a diverse range of softgel products that meet high standards of safety and efficacy, fast becoming synonymous with excellence in softgel formulations.Chris highlights the strengths Douglas offers as a CDMO partner, noting, “Few pharmaceutical companies can consistently deliver high-quality softgel capsules, leading many to exit the market due to quality issues. However, we’ve managed to maintain our market share in both the US and Europe, thanks to the superior quality of our products and the expertise of our team.” He credits the company’s technical expertise, technological capabilities, and stringent quality control processes as central to its success.
Quality is paramount in the production of softgel formulations and is a crucial consideration for companies seeking to engage a CDMO partner. Chris emphasizes, “Our team’s vigilance in all areas of production – from development to manufacturing to market quality surveillance, whether for novel or generic drug production – provides a significant advantage for our clients.” He further explains that Douglas’s strict adherence to quality control protocols, including cleaning, cross-contamination validation, and safety procedures for handling toxic compounds, makes the company a highly competitive CDMO partner.
Douglas CDMO can engage with companies at various stages of drug development, from early formulation to later stages in a product’s life cycle. For both novel and generic compounds, Chris advises companies to involve Douglas CDMO early in the formulation development process to ensure the most bioavailable and stable formulation is used in clinical studies. “We have extensive experience with early-stage product development. We can support our clients through first-in-human trials, registrational studies, and guide them in the supply of commercial products,” he concludes.
Learn more at www.douglascdmo.com
