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Related Concept Videos

Pharmaceutical Alternatives: Polymorphic Form-Related and Particle Size-Related Therapeutic Nonequivalence01:27

Pharmaceutical Alternatives: Polymorphic Form-Related and Particle Size-Related Therapeutic Nonequivalence

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Changes in polymorphic forms can significantly influence the bioavailability of poorly soluble drugs. Although the FDA defines pharmaceutical equivalence based on having the same active ingredient, dosage form, and route of administration, it does not automatically disqualify products with different polymorphic forms. This means two products with different polymorphs can still be deemed pharmaceutically equivalent. However, polymorphic differences can affect properties like wettability,...
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Factors Influencing Drug Absorption: Pharmaceutical Parameters01:28

Factors Influencing Drug Absorption: Pharmaceutical Parameters

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Solid dosage forms such as tablets and capsules undergo rigorous manufacturing processes to ensure stability and effectiveness. Their dissolution and absorption properties are influenced significantly by the choice of excipients (inactive ingredients that serve various roles in the formulation), and the methodology applied during production. The manufacturing parameters, such as compression force and granulation techniques, significantly affect dissolution rates. Elevated compression forces...
249
Formulation and Manufacturing Process: Physical Attributes of Generic Tablets and Capsules01:18

Formulation and Manufacturing Process: Physical Attributes of Generic Tablets and Capsules

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Bioequivalence in generic drugs, such as tablets and capsules, refers to their pharmaceutical equivalence to the brand-name counterparts. However, for therapeutic equivalence, manufacturers must also consider physical attributes like size, shape, and weight (FDA Guidance for Industry, December 2003). Discrepancies in these aspects could impact patient compliance and cause medication errors. For instance, swallowing difficulties, often experienced with larger tablets or capsules, can lead to...
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Factors Influencing Drug Absorption: Drug Dissolution01:27

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The pharmacokinetic journey of drugs from solid oral dosage forms into systemic circulation is multifaceted. It begins with disintegration, a prerequisite ensuring a solid dosage form's subdivision into minute particles. Dissolution occurs next as these granulated entities solubilize in gastrointestinal fluids. This solubilization is crucial for the succeeding stage, permeation, which describes the traversal of the drug across the intestinal membrane and its subsequent entry into the blood...
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Factors Affecting Dissolution: Polymorphism, Amorphism and Pseudopolymorphism01:21

Factors Affecting Dissolution: Polymorphism, Amorphism and Pseudopolymorphism

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Polymorphism refers to the existence of a drug substance in multiple crystalline forms, known as polymorphs. Recently, this term has been expanded to include solvates (forms containing a solvent), amorphous forms (non-crystalline forms), and desolvated solvates (forms from which the solvent has been removed).
Some polymorphic crystals possess lower aqueous solubility than their amorphous counterparts, leading to incomplete absorption. For instance, the oral suspension of Chloramphenicol, which...
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Dosage Regimen: Fixed Dose01:01

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Fixed-dose regimens are a common approach to administer drugs to achieve and maintain desired levels of the drug in the body. In this dosing strategy, a specific amount of medication is given at regular intervals, often multiple times a day, to ensure a consistent drug concentration in the bloodstream.
Fixed-dose regimens can be used for various routes of administration, including intravenous (IV) injections and oral medications. For IV administration, a predetermined amount of the drug is...
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Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs.

Deanna M Mudie1, Aaron M Stewart1, Jesus A Rosales1,2

  • 1Global Research & Development, Lonza, Bend, OR 97703, USA.

Pharmaceutics
|April 30, 2021
PubMed
Summary

A new amorphous solid dispersion (ASD) tablet formulation improves acalabrutinib exposure, overcoming issues caused by acid-reducing agents. This enhances treatment efficacy and patient compliance for this tyrosine kinase inhibitor.

Keywords:
acalabrutinibacid-reducing agentamorphous solid dispersionbioavailability enhancementkinase inhibitorpH effectproton pump inhibitorspray drying

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Area of Science:

  • Pharmaceutical Sciences
  • Drug Delivery Systems
  • Pharmacokinetics

Background:

  • Calquence (acalabrutinib), a tyrosine kinase inhibitor (TKI), shows reduced oral exposure with acid-reducing agents (ARAs) due to its weak base nature and low solubility at high gastric pH.
  • This pH-dependent drug-drug interaction (DDI) necessitates strict dosing, impacting patient treatment and quality of life.

Purpose of the Study:

  • To develop and evaluate an amorphous solid dispersion (ASD) formulation of acalabrutinib to overcome pH-dependent absorption limitations.
  • To improve oral bioavailability and reduce the impact of DDIs associated with ARAs.

Main Methods:

  • Formulation of an immediate-release (IR) tablet using a spray-dried ASD containing 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade).
  • In vitro multicompartment dissolution testing to predict in vivo performance.
  • In vivo pharmacokinetic study in beagle dogs comparing ASD tablets with Calquence capsules at low and high gastric pH.

Main Results:

  • ASD tablets maintained similar plasma drug exposure (AUC) across low and high gastric pH conditions.
  • ASD tablets demonstrated a 2.4-fold higher exposure than Calquence capsules at high gastric pH in beagle dogs.
  • In vitro dissolution testing successfully predicted the improved in vivo performance of the ASD formulation.

Conclusions:

  • Spray-dried ASD technology effectively overcomes the reduced oral exposure of acalabrutinib caused by high gastric pH.
  • ASD tablets offer a promising approach to improve patient compliance and therapeutic efficacy for acalabrutinib and other weakly basic drugs with pH-dependent absorption.
  • The developed ASD formulation exhibited favorable manufacturability, physical stability, and chemical stability, along with a reduced tablet size.