Capsules and Gelatin Overview

Capsules

• Capsules enclose one or more medicinal substances in a hard or soft gelatin shell.
• Capsules offer several advantages over other dosage forms, including:
  • Fewer formulation problems arise due to the simplicity of incorporating active ingredients into capsules, minimizing the challenges related to compatibility and stability encountered in tablet formulations.
  • Better stability compared to tablets
  • Reproducible disintegration refers to the consistent and predictable breakdown of capsules into their constituent parts within the gastrointestinal tract. This characteristic is crucial for ensuring that active pharmaceutical ingredients (API) are released effectively and absorbed by the body when the capsule is ingested. Unlike solid dosage forms that may have varying disintegration times due to their composition, capsules provide a more uniform disintegration profile, allowing for a reliable onset of action. Furthermore, this reproducibility is essential for achieving therapeutic effectiveness, as it minimizes variability in how the drug performs from one dosage to another. Such consistency can significantly impact treatment outcomes, especially in therapeutic regimens requiring precise dosing and timing.
  • By employing fewer ingredients in the formulation of capsules, there is a significant reduction in potential drug interactions. This simplification helps to enhance the bioavailability of the active substances, ensuring more effective therapeutic outcomes for patients.
  • Convenient dosage form for solids and liquids
• Disadvantages of capsules include:
  • This refers to the difficulty in achieving consistent weight and dosage accuracy in capsules.
  • Capsules are designed for convenience and efficacy; however, it's important to note that they are not inherently tamper-proof. This means that unlike some other pharmaceutical dosage forms, which may feature child-resistant or tamper-evident packaging, capsules can be easily opened or altered.
  • The manufacturing process for capsules can be intricate and resource-intensive, leading to elevated costs. Factors contributing to high production costs include the price of raw materials, the complexity of the machinery required for capsule formulation, and the stringent quality control measures needed to ensure safety and efficacy. Additionally, the need for specialized labor to operate sophisticated equipment may also play a role in driving costs upward.

Raw Materials

• The main raw materials for gelatin capsules are animal-derived gelatin, water, colorants, and optional preservatives. Same for soft and hard.
• Gelatin, water, colourants, and optional preservatives are common components.
• Soft gelatin capsules often include plasticizers.
• Gelatin solution preparation is followed by the addition of colourants, preservatives, and process aids, adapting to the specific capsule type.

Gelatin

• Gelatin is the primary component of capsules.
• It exhibits five key properties that make it suitable for capsules:
  • Non-toxic, promoting widespread use.
  • Readily soluble in biological fluids at body temperature.
  • Forms strong, flexible films.
  • High-concentration solutions (40% w/v) demonstrate excellent fluidity when maintained at a temperature of approximately 50 degrees Celsius, enhancing processing efficiency.
  • Undergoes reversible sol-to-gel phase changes, transitioning at temperatures only a few degrees above ambient.
• Gelatin is naturally occurring but is prepared through collagen hydrolysis (a protein in animal connective tissues, including bones and skins).

Plasticizers

• Soft gelatin capsules require flexibility, achieved through plasticizer addition.
• Plasticizers increase flexibility.
• The proportion of plasticizers affects the capsule's characteristics (e.g., glycerol, sorbitol, propylene glycol, acacia).

Colourants

• Colourants for capsules come in two types: soluble dyes and insoluble pigments.
• Mixtures of dyes and pigments create various colours.
• Their use is strictly monitored to ensure safety, efficacy, and compliance with health regulations, preventing adverse effects. Colour legislation

Preservatives

• Preservatives prevent microbial contamination during capsule production.
• Finished capsules have low moisture content, hindering microbial growth.
• Soft gelatin capsules often incorporate antifungal agents to effectively prevent fungal contamination and surface growth during storage, especially when they are not sealed or protected, ensuring the integrity and safety of the product.

Hard Gelatin Capsules

• Hard capsule shells are produced by dipping molds into gelatin solution, drying the resulting film, cutting to length, and stripping from the mold.
• Hard capsules are available in various sizes, enabling flexible dosing options for different formulations. Size 000 is the largest, accommodating more significant quantities of medication, while size 5 is the smallest, ideal for concentrated doses or powdered ingredients.
• The calculation of capsule fill weight is crucial for ensuring accurate dosing and efficacy of the medication contained within the capsule. By multiplying the tapped bulk density, which represents the mass of a substance per unit volume after being compacted, by the capsule's volume, manufacturers can determine the appropriate size and fill weight needed for optimal performance and patient compliance.

Filling

• Capsule fill materials play a vital role in the efficacy of drug formulations. They must not only be accurately dosable to ensure consistent therapeutic outcomes, but they also need to effectively release active components in a form that the body can easily absorb and utilize, enhancing patient compliance and treatment success.

Both dry solids and semi-solids (e.g., pastes, thixotropic mixtures) can be used in hard gelatin capsules.

Formulation Aspects

• Capsule formulations may involve powders, non-powders (minitablets, granules, pellets), or semi-solids.
• Diluents enhance powder flow characteristics, which is particularly important for achieving uniform filling in low-dose drug formulations., including maize starch and spray-dried lactose.

Glidants are excipients commonly used in the formulation of powdered substances, particularly in the pharmaceutical industry. Their primary function is to improve the flow properties of powders during the manufacturing process, which is crucial for ensuring uniformity and consistency in capsule or tablet filling. These substances help minimize friction between particles, reducing clumping and promoting smooth movement through machinery.

• Common examples of glidants include magnesium stearate and colloidal silicon dioxide.

• Glidants (up to 5% w/w), like colloidal silicon dioxide, enhance flowability for high-dose formulations, allowing for improved processing and consistent filling during production.

• Lubricants (e.g., magnesium stearate) reduce powder-metal adhesion.

• Wetting agents are substances that facilitate the spreading and penetration of liquid formulations on solid surfaces. Common wetting agents include surfactants such as polysorbates and sodium lauryl sulfate. Incorporating wetting agents in capsules enhances drug dissolution rates and therapeutic efficacy. Play a vital role in enhancing drug solubility, thereby promoting more efficient drug release from the dosage form.

Bioavailability Aspects

• Capsule absorption is generally faster than tablet absorption, provided gastric and intestinal fluids reach the contents after shell rupture.
• Factors influencing absorption include formulation components (e.g., drug particle size, glidant hydrophobicity) and preparation methods.

Soft Gelatin Capsules

• Soft gelatin capsules consist of a single-piece outer gelatin shell enclosing a liquid or semi-solid matrix.
• Capsule filling materials are solutions or suspensions.

Capsule formation, filling, and sealing occur in a single operation.

• Available in various sizes and shapes, including round, oval, oblong, and tubes.

Testing

• Capsule testing involves several key stages:
  • Uniformity of fill weight is crucial in pharmaceutical manufacturing to ensure that each dosage form, such as a capsule or tablet, contains the intended amount of active pharmaceutical ingredient (API). This consistency is vital for ensuring effective and predictable therapeutic outcomes. Variability in fill weight can lead to underdosing or overdosing, which can compromise patient safety and treatment efficacy. Manufacturing processes must be optimized and monitored closely for fill weight uniformity, employing techniques such as gravimetric analysis and advanced filling machinery to maintain stringent quality control standards.
  • Disintegration tests
  • Dissolution tests
  • Content uniformity
  • • The assay of active ingredients involves quantitative analysis methods to determine the concentration and purity of the active pharmaceutical ingredients (APIs) present in a formulation.. Common techniques include high-performance liquid chromatography (HPLC), gas chromatography (GC), and spectrophotometry. These methods help identify any impurities or degradation products that may affect the performance of the drug.
  • Related substances, also referred to as impurities, are unintended compounds that may co-occur with the active pharmaceutical ingredient (API) during the manufacturing process. Their analysis is crucial for ensuring the safety, efficacy, and quality of pharmaceutical products. Techniques such as high-performance liquid chromatography (HPLC), gas chromatography (GC), and mass spectrometry (MS) are commonly used to identify and quantify these impurities.
  • Microbiological testing.

Liquid Vehicles

• Liquid vehicles can include both volatile and non-volatile oils (vegetable, fixed, aromatic), hydrocarbons, liquid ethers, esters, and water-miscible liquids (PEGs, alcohols, triacetin).
• Suspensions are used to incorporate insoluble drugs, and suspending agents (wax, cellulose, and surfactants to promote wetting) are often incorporated.