ABSTRACT
Ligustrazine (or Tetramethylpyrazine, TMP) is an active pharmaceutical ingredient that faces the challenges of bitter taste and low oral bioavailability by the commercial phosphate salt (TMP-Pho). We tackled these challenges by forming salts with two sweeteners, acesulfame (Acs) and saccharine (Sac). Both salts effectively masked the bitter taste of TMP. Compared to TMP-Pho, TMP-Sac shows 43% lower solubility and 11% lower permeability while TMP-Acs shows higher (two-fold) solubility but 24% lower permeability. Both TMP-Acs and TMP-Sac exhibited approximately 40% higher bioavailability through reducing the rate of TMP absorption. Thus, salt formation with both sweeteners simultaneously addressed the challenges brought about by the bitter taste and lower bioavailability of TMP.
Subject(s)
Pyrazines/administration & dosage , Sweetening Agents/chemistry , Taste , Administration, Oral , Adult , Animals , Biological Availability , Double-Blind Method , Female , Humans , Male , Permeability , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Saccharin/chemistry , Solubility , Thiazines/chemistry , Young AdultABSTRACT
As a result of its higher molecular mobility, the surface of an amorphous drug can grow crystals much more rapidly than the bulk, causing poor stability and slow dissolution of drug products. We show that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous indomethacin by electrostatic deposition, leading to significant improvement of physical stability, wetting by aqueous media, dissolution rate, powder flow, and tabletability. The coating condition was chosen so that the positively charged polymer deposits on the negatively charged drug. Chitosan coating is superior to gelatin coating with respect to stability against crystallization and agglomeration of coated particles.
Subject(s)
Chemistry, Pharmaceutical/methods , Chitosan/chemistry , Drug Compounding/methods , Drug Liberation/physiology , Drug Stability , Indomethacin/chemistry , Polymers/chemistry , Crystallization , Drug Interactions , Gelatin/chemistry , Humidity/adverse effects , Powders/chemistry , Solubility , Static Electricity , Surface Properties , Tablets/chemistry , Tensile Strength , X-Ray DiffractionABSTRACT
A palatable direct compression (DC) orally disintegrating tablet (ODT) product of a bitter drug, diphenhydramine (DPH), was developed using an integrated crystal and particle engineering approach. A DPH salt with a sweetener, acesulfame (Acs), DPH-Acs, was synthesized and its solid state properties were comprehensively characterized. Tablet formulation composition and compaction parameters were optimized by employing material sparing techniques. In vivo disintegration time, bitterness, and grittiness of the final ODT product, were evaluated by a taste panel. Physical stability of the ODT tablets was assessed to identify appropriate storage conditions. Phase-pure DPH-Acs exhibited significantly better tabletability and palatability than DPH-HCl. A DC formulation was designed and optimized to obtain a new ODT product with good manufacturability and excellent product characteristics, including fast in vivo disintegration, and acceptable bitterness and grittiness. A new ODT product of DPH with excellent pharmaceutical properties was successfully developed using 15 g of DPH and in two months. This example shows that integrated crystal and particle engineering is an effective approach for developing high quality ODT products using the DC process.
Subject(s)
Chemical Engineering/methods , Diphenhydramine/administration & dosage , Drug Compounding/methods , Histamine H1 Antagonists/administration & dosage , Taste , Administration, Oral , Chemistry, Pharmaceutical , Drug Stability , Excipients/chemistry , Hardness , Solubility , Tablets , Thiazines/chemistryABSTRACT
Salt formation has been extensively used to improve drug properties, including solubility, stability and mechanical properties. A sweet salt of metformin with acesulfame, prepared though an anion exchange reaction, showed superior properties over the commercial hydrochloride salt. These included both remarkable improvement of taste and significant enhancement in tabletability, which is explained by the different crystal structures and lower hardness as measured by nanoindentation. The relationship among crystal structure, mechanical properties and tabletability was rationalized through an energy framework analysis. This approach led to the successful development of an orally disintegrating tablet product containing 60% of metformin-acesulfame salt by direct compaction.
