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API Particle Size distribution in Tablet

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Determination ofAPI Particle Size in Formulation

The efficacy of a dosage form depends on physicochemical properties of the active pharmaceutical ingredient (API). Mainly physical properties like Particle size, shape, and solid-state form of the API and its arrangement in the excipients matrix control the rate of dissolution, bioavailability and stability of the oral solid dosage from. Particle size is inversely proportional to the surface area as the particle size is decreased the surface area is increased.

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Agglomeration in API

Particle Size Evaluation

Particle size can be evaluated by many techniques but only general techniques are listed below

  • Microscopy and image analysis
  • Sifting
  • Laser diffraction
  • Dynamic light scattering (DLS)

The API is often micronized prior to the formulation or it may be micronized during the formulation, and its size is tightly controlled. However, API size after micronization does not always reflect its size in a complex dosage matrix. The particles of API undergo mechanical stresses during formulation processes such as mixing, sifting, granulation, drying, blending, tableting, and coating and even during storage of the final product, depending on its formulation and packaging. During pharmaceutical production, controlling the particle size of API and other excipients is a critical parameter to ensure product quality. However, API particle size in multiple components cannot be specifically assessed using the aforementioned devices.

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Challenges for Characterization of API Particle Size in Formulation

Determination of API particle size in the excipients matrix of the final product is a major challenge in pharmaceutical development. One of the main challenges is irregular shape (Nonspherical) of many pharmaceutical substances (especially APIs) which leads to complex data interpretation. The other challenges include agglomeration, instability and other physicochemical changes occur during measurement.

Regulatory Issues

The ICH Guidelines explicitly states that particle size is one of the physicochemical properties influencing the performance of the drug product and its manufacturability (https://www.ich.org). Further specifications are described in ICH Q6A acceptance criteria in new drug substances for solid or suspension drug products. The decision tree is reflected below for setting acceptance criteria for drug substances (API) particle size distribution (Fig-1).

Equivalent Particle Diameter (Equivalent Particle size)

The general terminology of particle size itself is ambiguous especially for nonshperical particles, as theoretically particle size is defined as “characteristic linear dimension”, which fits only for spherical particles. In addition to that all the instrumental techniques (Except microscopic techniques) won’t measure the particle size directly as the data obtained is physical response in relation to the size and shape of the particles. As per the data available it can be stated that for spherical particles the deviation would be within 10% whereas for nonspeherical particles it would be higher because most of the sizing methods are devised for spherical particles and seldom discriminate between different shapes.

In the purview of aforesaid limitations for measuring techniques, the concept of equivalent particle diameters has been introduced. Equivalent particle diameter is a correlation of irregularly-shaped particle to equivalent spherical particle. Equivalent Particle Diameter will take into account of particle shape and particle dispersion. In addition to that all the instrumental techniques (Except microscopic techniques) won’t measure the particle size directly as the data obtained is a physical response of the device in relation to the size and shape of the particles.

Strategy Adopted by Nishka

We at Nishka Research have developed our own (Proprietary) in-house protocols to evaluate the API particle size in formulation. We generally deploy 3-4 imaging techniques, which are described below. In a nut shell we use any of individual techniques or a hybrid technique which is a combination of more than one technique.

    • Optical microscopic (Transmitted and reflected) technique with data processing algorithm (AI enabled).
    • Hot stage microscopy with data processing algorithm (AI enabled).
    • SEM (Scanning Electron Microscope) technique with data processing algorithm (AI enabled).
    • TEM (Transmission Electron Microscope) technique with data processing algorithm (AI enabled).

Every technique has its own advantages & limitations as these techniques are product specific therefore selection of technique is purely based on feasibility study.

Data Interpretation and Presentation

The reports generated by Nishka Research for characterization of API particle size in formulation, reflect the unique blend of algorithm with empirical calculations and it may not be exaggerated if it is stated as “HYPER REALISTIC”. Our API particle size and shape characterization report comprises both the size measurement and the quantitative description of physical properties of the particulate matter accompanied with careful data interpretation.

Frequently Asked Questions

How does the particle size of the excipients used in tablet formulation impact API particle size?
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The particle size of the excipients used in tablet formulation can impact the API particle size through processes such as granulation and blending. Excipients with larger particle sizes may require more forceful processing to ensure proper mixing, which can alter API particle size.
How does API particle size impact the physical and chemical stability of the tablet formulation?
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API particle size can impact the physical and chemical stability of the tablet through effects on properties such as surface area, reactivity, and solubility. Smaller particle sizes can lead to increased surface area and reactivity, which can lead to degradation of the API.
What is the relationship between API particle size and tablet compression force?
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The compression force required to form a tablet can increase with decreasing API particle size, as smaller particles may require greater force to compact into a cohesive tablet.
How do different API particle size distributions impact tablet properties?
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Different API particle size distributions can impact tablet properties such as dissolution rate, content uniformity, and stability. Narrower particle size distributions can result in more consistent tablet properties.
How do particle size specifications differ for immediate release versus extended release tablets?
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Particle size specifications may differ for immediate release versus extended release tablets, as the dissolution rate requirements may be different. Extended release tablets may require a different particle size distribution to ensure consistent release of the API over time.
How can particle size measurements be used to optimize tablet manufacturing processes?
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Particle size measurements can be used to optimize tablet manufacturing processes by ensuring consistent particle size distribution of the API and excipients, which can lead to more consistent tablet properties.
What is the relationship between API particle size and tablet disintegration time?
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API particle size can impact tablet disintegration time by affecting the rate at which the tablet breaks down in the presence of water. Smaller particle sizes may lead to faster disintegration times.
How do API particle size specifications differ for tablets versus capsules?
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API particle size specifications may differ for tablets versus capsules due to differences in formulation and manufacturing processes. Capsules may require a narrower particle size distribution to ensure consistent fill weight.
How do particle size measurements differ for poorly soluble versus highly soluble APIs?
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Particle size measurements may differ for poorly soluble versus highly soluble APIs due to differences in the dissolution behavior of the particles. Poorly soluble APIs may require a narrower particle size distribution.
What are the common sources of variability in API particle size measurements?
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Common sources of variability in API particle size measurements include differences in sample preparation, instrument calibration and measurement technique.
How do environmental factors, such as temperature and humidity, impact API particle size measurements?
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Environmental factors can impact the properties of the API and excipient particles, which can in turn impact the accuracy of the particle size measurement. For example, high humidity can cause particles to stick together and appear larger than they actually are.

Why ChooseNishka Research

Nishka Research has decades of experience in working similar kind of studies for diversified products. Our multidisciplinary subject matter experts are well versed with your requirement and can design the protocol which will be a value addition. We have a holistic strategy that will enable you in thorough understanding of product development and its requirement. What are excipients and their physicochemical properties and how they impact the product? There by you will have insights of how the API is distributed in the excipients matrix.

Nishka Research Offers API Particle Size / Globule Size Characterization Studies for Below Formulations:

  • Solid oral dosage form (Tablets)
  • Suspensions
  • Emulsions
  • Ointments
  • Lotions

 

Looking for a trusted partner to achieve your research goals? schedule a meeting with us, send us a request, or call us at +91 78427 98518 to learn more about our services and how we can support you.

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