Metformin Hydrochloride and Sitagliptin Phosphate Fixed Dose Combination Product Prepared Using Melt Granulation Continuous Processing Technology

Jeremiah Kelleher, Atif Madi, Gareth C. Gilvary, Justin Tian, Shu Li, Ammar Almajaan, Zoe Senta Loys, David Jones, Gavin Andrews, Anne Marie Healy

Research output: Contribution to journalArticle

Abstract

The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80% w/w and 6% w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet®, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.
Original languageEnglish
Number of pages14
JournalAAPS PharmSciTech
Volume21
Issue number1
DOIs
Publication statusPublished - 12 Dec 2019

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Metformin
Dosage Forms
Technology
Freezing
Tablets
Temperature
Polymers
Pharmaceutical Preparations
Weights and Measures
Transition Temperature
Particle Size
Glass
Sitagliptin Phosphate

Keywords

  • continuous manufacturing
  • fixed-dose combinations
  • high-dose compounds
  • hot melt extrusion
  • melt granulation

Cite this

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title = "Metformin Hydrochloride and Sitagliptin Phosphate Fixed Dose Combination Product Prepared Using Melt Granulation Continuous Processing Technology",
abstract = "The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80{\%} w/w and 6{\%} w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet{\circledR}, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.",
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Metformin Hydrochloride and Sitagliptin Phosphate Fixed Dose Combination Product Prepared Using Melt Granulation Continuous Processing Technology. / Kelleher, Jeremiah; Madi, Atif; Gilvary, Gareth C.; Tian, Justin; Li, Shu; Almajaan, Ammar; Senta Loys, Zoe; Jones, David; Andrews, Gavin; Healy, Anne Marie.

In: AAPS PharmSciTech, Vol. 21, No. 1, 12.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metformin Hydrochloride and Sitagliptin Phosphate Fixed Dose Combination Product Prepared Using Melt Granulation Continuous Processing Technology

AU - Kelleher, Jeremiah

AU - Madi, Atif

AU - Gilvary, Gareth C.

AU - Tian, Justin

AU - Li, Shu

AU - Almajaan, Ammar

AU - Senta Loys, Zoe

AU - Jones, David

AU - Andrews, Gavin

AU - Healy, Anne Marie

PY - 2019/12/12

Y1 - 2019/12/12

N2 - The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80% w/w and 6% w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet®, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.

AB - The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80% w/w and 6% w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet®, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.

KW - continuous manufacturing

KW - fixed-dose combinations

KW - high-dose compounds

KW - hot melt extrusion

KW - melt granulation

U2 - 10.1208/s12249-019-1553-2

DO - 10.1208/s12249-019-1553-2

M3 - Article

VL - 21

JO - AAPS PharmSciTech

JF - AAPS PharmSciTech

SN - 1530-9932

IS - 1

ER -