Formulation and evaluation of immediate release tablets with different types of paroxetine hydrochloride powders prepared by direct compression

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About Authors:
Nishant Gupta
Department of pharmaceutics,
B.N. College of pharmacy,

Paroxetine (PRX) crystals exhibit poor compressibility, poor flowability and its tablets show a tendency to cap. To improve the mechanical strength of tablets several kinds of “Paroxetine for direct compression” are present on the market. Current research demonstrated the best tablet properties with coated paroxetine (mass of tablets, diameter, height and mechanical strength, friability RSD<2%). Furthermore, coated paroxetine in combination with both investigated superdisintegrants such as Vivasol® and Polyplasdone® XL-10 shows faster disintegration time and dissolution rate in comparison to paroxetine for direct compression. Eventually, the major advantages of the formulation with coated paroxetine for industrial production are decrease of friability and superiority in terms of flowability, compressibility, quick disintegration and dissolution. Regarding the results, coating of PRX particles is beneficial for the manufacturing of tablets with immediate release.

Reference Id: PHARMATUTOR-ART-1199

Paroxetine (3S,4R )-3-[(1,3-benzodioxol-5-vloxy)methyl]- 4-(4-europhenyl) piperidine is one of the most widely usedis a new generation antidepressant drug. It exerts its antidepressant effect through a selective inhibition for the reuptake of the neurotransmitter serotonin by the presynaptic receptors. PRX is comparable to the tricyclic antidepressants in their clinical effcacy, however, PRX is safer and has greater acceptance by the patients. (Quellet and Percival, 2001). PRX is usually formulated in tablets containing 10 to 40 mg of drug (Martinello et al., 2006). The most appropriate technology for industrial production of tablets is direct compression. In practice, direct compression has been limited mainly to formulation containing small proportions of the active ingredient and appropriate compressibility. The advantages of the direct compression are primary reduced production cost, better product stability and faster dissolution of API when compare to process of granulation (Aulton, 2007). In terms of inadequate compressibility, powder properties can be improved by the addition of binders (Nystrom et al., 1982; Kolter and Flick, 2000). Dry binders can be utilized to improve tablet strength, especially when the interparticulate bonds between the compound crystals are weak (Eichie and Amalime, 2007; Ngwuluka et al., 2010). PRX crystals exhibit poor compression ability, low flowability and its tablets show great tendency to cap. The poor compaction behavior of PRX and its elastic deformation has been related to different PRX polymorphic forms.
Even though they are chemically identical, the different polymorphic forms show different free energies, and different physical properties that can significantly influence product performance. These include differences in solubility and dissolution rate (affecting bioavailability), solid-state stability (affecting potency), deformation characteristics (affecting compressibility), and particle size and shape (affecting powder density and flow properties) (Martinello et al., 2006). There are several methods for modification of the crystalline structure of PRX, in order to manufacture tablets via direct compression.
Examples include spherical crystallization, crystallization from different solvents to produce different crystal habits, incorporation of additives by co-precipitation, development of sintered-like crystals and co-extrusion with isomalt (Di Martino et al., 1996; Fachaux et al., 1995; Garekani et al., 2000; Ndindayino et al., 2001). Untreated PRX particles show massive elastic deformation under pressure which results in axial expansion of tablet in the phase of decompression. As a consequence, tablets often express different types of mechanical strength problems such as capping, chipping, lamination, stress cracking, and sticking as well as picking (Wu et al., 2007).
To improve the mechanical strength of tablets with PRX, several PRXs for direct compression (D.C.) are present in the market. These materials provide sufficient flowability and compactability. PRX for D.C. is modified with different binders, but it still shows optimal dissolution rate, which is necessary for development of tablets with immediate release profile (Fachaux et al., 1995; Kulkarni and Amin, 2008; Okoye et al., 2009). Despite the increasing interest in controlled release drug delivery systems, the most desired forms of tablets are those intended to be swallowed whole. They subsequently disintegrate and release their active ingredient rapidly in the gastrointestinal tract (GIT) (Zhao and Augsburger, 2005a).
Tablets for immediate release often consist of filler, a binder, lubricants and disintegrants (Fukami et al., 2006). In many cases, the disintegration time of solid dosage forms is too long to provide appropriate therapeutic effect. To improve the disintegration time, so-called disintegrants are used. The most accepted mechanisms of their action are wicking, swelling, deformation recovery and particle repulsion. Together, these phenomena create a disintegrating force within the matrix (Zhao and Augsburger, 2005b). In the past, non-modified disintegrants were used to accelerate disintegration, that is, alginates, starches, ambrelite resins, cellulosic materials, pectines and others. Today, a fast working superdisintegrant is chemically modified, typically by crosslinking the organic chains of a polymeric molecules. Three classes of superdisintegrants are commonly used: modified cellulose (croscarmellose sodium - Ac-Di-Sol®, Vivasol®), crosslinked polyvinyl pyrrolidone (Polyplasdone® XL-10) and modified starch (Sodium Starch Glycolate – Primojel®, Explotab®). The basic objective of this study was to produce immediate release tablets containing different types of PRX via direct compression, to compare their properties, disintegration and dissolution profiles. PRX was used as a model drug for immediate release tablets because of its primary indication in treatment of pain where the effect of drug should be rapid. To reach this goal, it is necessary to find a suitable disintegrants having excellent compactability and disintegrating properties. Furthermore, we were focus on establishing differences between PRX powders and to examine how their characteristics influence the tablet manufacture and dissolution profiles. Finally, we wanted to elaborate, whether the coating of PRX particles has a beneficial effect for manufacturing of tablets with immediate release.


PRX (monoclinic form, Huzhou Konch Pharmaceuticals Co. Ltd.), PRX D.C. (Mallinckrodt inc. St.Louis, USA) and PRX coated (Ethypharm SA, France) were chosen as active ingredients; (Figure 1) Kolidon® VA 64 (Maharashtra, India) and Klucel® - EXF (Maharashtra, India) were used as binders; Polyplasdone® XL-10 (Maharashtra, India) and Vivasol® (Maharashtra, India) were used as superdisintegrants; Avicel® PH 200 (Maharashtra, India) was used as a filler, Mg-stearate (Maharashtra, India) and Aerosil® 200 (Maharashtra, India) were utilized as glidants. Paxil® (Hemopharm concern, Stada, Germany) was chosen as reference tablet.

Powder properties
True, bulk, and tapped density
The true densities of the powder mixtures were determined by helium picnometry (Accupyc 1330, Microneritics, Norcross, Ga., USA). Three samples of each mixture were analyzed, each sample was read three times, and the overall means were calculated. Bulk density measurements were carried out using flat – ground measuring cylinder with a volume of 250 ml. The cylinder was filled with the specified mass of powder mixture and unsettled apparent volume V0 was read to the nearest millilitre. After 10, 250, 500, 1250 taps the corresponding volume was read to the nearest millilitre. The tapped volume was recorded when the difference between the two volumes was smaller than 1 ml For PRX D.C., PRX coated, and tablet powder mixtures, V1250 was used. The tapped density was determined on a tapped volume determination apparatus (Vankel apparatus, Van Kel Technology Group, Edison, NJ, USA).

Apparent density before settling or density of bulk product:

ρ = m/V0 [g/ml]                                         (1)

Apparent density after settling or density of settled product:

ρ = m/V1250 or [g/ml]                                  (2)

Figure 1. Scanning electron micrographs of different paroxetine powders (a - monocrystalline paroxetine; b - paroxetine D.C; c - coated paroxetine).



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