Formulation Development and Compaction of Itraconazole Amorphous Solid Dispersions Tablet Using Quality by Design Principles
Itraconazole (ITZ), a BCS Class II drug exhibiting low solubility (1-4 ng/ mL in water) requires formulation enhancement to achieve enhanced bioavailability. To tackle this problem amorphous solid dispersions (ASDS) of ITZ in a polymer matrix (Kollidon® VA64) were produced using the Hot Melt Extrusion (HME) process. ASDS improve the poor solubility of the BCS Class II drug, compared to its pure crystalline form, however this enhancement is impaired at the tableting stage due to the high dose (100 mg) requirement and the presence of high polymer content (70%).
In this study, a fast-screening approach to formulation development using the STYL’One Nano compaction simulator was adopted. Initially number of preliminary formulations were compacted, followed by the introduction of a novel strategy using salts to enhance the disintegration and dissolution properties. Five inorganic salts were investigated, sodium chloride (NaCl), potassium chloride (KCl), potassium bicarbonate (KHCO3), potassium dihydrogen orthophosphate (KH2PO4) and potassium bromide (KBr). These kosmotropic salts are debated to compete for water hydration near the polymer chain, hence preventing polymer gelation and therefore facilitating disintegration and dissolution [1].
Experimental Design
The quality target product profile (QTPP) was proposed for immediate release ITZ ASD (30%) tablets with 100 mg dose, followed by identification of the critical quality attributes (CQAs), i.e. tensile strength (>1.7 MPa), solid fraction (80-90%), disintegration time (<15 minutes) and friability (<1%) through risk assessment (Figure 1).
The Zoomlab™ software (BASF, Germany) was initially utilised to determine potential excipients for an ITZ tablet formulation as a starting point. Formulation suggestions for ITZ and KVA64 included, diluents such as Avicel pH102® (MCC), Ludipress®(LUD) and Tablettose®70 (TAB70), along with the disintegrant Kollidon®-CL-SF (KOLSF). Other common disintegrants such as croscarmellose sodium (CrNa) and magnesium stearate (MgSt) as lubricant, reported in literature [2] were also incorporated. To achieve the CQA targets, firstly disintegrant type (KOLSF and CrNa at 4%) was explored, followed by decreasing the percentage of ASD in the tablet (83.3 to 33.3%), increasing the disintegrant level (4 to 7.5% KOLSF) and adding soluble excipients (LUD, TAB70 and inorganic salts) (Figure 2).
The final strategy involved compacting five inorganic salts, KCl, NaCl, KH2PO4, KHCO3 and KBr as described in Table 1 (750 mg tablets). Compaction was carried out using compression pressures of 50, 100, 150, 200 and 250 MPa, using the Euro D round (ø =11.28mm) punch and a V-shape profile. Tablet testing was conducted using the SmartTest 50 (Sotax, UK) hardness tester. The disintegration time of the inorganic salt tablets compacted at 200 MPa was compared. Dissolution of an optimised formulation (750 mg) with 11.9% KCl, 31.3% MCC and 14.4% TAB70 was compared with an ASD formulation without KCl (ASD-KCl) and a physical mixture formulation with KCl (PM+KCl).
Results
Preliminary formulation enhancement strategies
During preliminary stages of formulation, it was found that neither the KOLSF nor CrNa promoted disintegration of 400 mg ITZ ASD tablets. As the ASD contains 70% Kollidon® VA64 this has a gelation effect which can prevent disintegration. By decreasing the amount of ASD from 83.3% (400 mg tablet) to 33.3% (1000 mg tablet) disintegration was possible. However, 1000 mg tablets would not be acceptable by many patients and so a final tablet weight of 750 mg was used to also meet the CQAs. Despite the reduced amount of ASD (44.4%), increased disintegrant (KOLSF at 7.5%) and replacement of LUD to a more soluble lactose, TAB70 the tablets did not disintegrate. A novel strategy using inorganic salts was therefore introduced to promote disintegration.
Compaction and disintegration of Inorganic Salt formulations
The tabletability plot (Figure 3) of the five salt tablets show low tensile strength (<1.7 MPa) below compression pressure of 200 MPa. This plot shows a suitable force within the linear region to be chosen with no tablet defects. The tabletability of a formulation usually increases with increasing pressure (linear region) which then gradually level off, despite the increase in pressure [3]. The KCl, KH2PO4, KHCO3 and KBr tablets required a higher force of 200 MPa to achieve a tensile strength higher than 1.7 MPa. NaCl tablets did not reach desired tensile strength even at high compression pressure of 250 MPa. All tablets containing salts achieved solid fraction between 80-90% which comply with the proposed QTPP.
The addition of inorganic salts accelerated disintegration significantly (Figure 4). The KHCO3 formulation disintegrated the slowest (15 minutes) which narrowly passes the CQA target. Four salts were comfortably within the target disintegration time, with NaCl disintegrating the fastest (2.29 minutes), followed by KCl and KH2PO4 (4 minutes) and finally KBr (6.4 minutes). NaCl demonstrated the quickest disintegration time but did not reach the desired tensile strength (1.56 MPa). The anions Cl-, PO4- , CO32- and Br- have large negative Gibbs free energy of hydration as they are kosmotropic and so have a structured water ‘lattice’ around the ion [4]. The salt prevents gelling of the polymer in the ASD by competing for water instead (salting-out effect) [2]. Interestingly, the anions efficiency did not strictly follow the proposed Hofmeister series for kosmotropic salts (CO32->PO4- >Cl-); similar findings have been reported in literature [4,5].
formulations.
KCl, KH2PO4 and KBr tablets achieved the desirable tensile strength (above 1.7 MPa at 200 MPa) whilst providing a quick disintegration time. The salt-polymer interactions effects have possibly modified the structure of water by the presence of ions beyond their hydration shells which impacted the disintegration mechanism and therefore allowing disintegration of ITZ ASD tablets [1]. All salt tablets achieved friability below 0.53%, which comply with the proposed QTPP. Out of the three salts which met the QTPP, an optimised formulation with 11.9% KCl (plus 44.4% ASD, 31.3% MCC, 14.4% TAB70, 7.5% KOLSF and 0.5% MgSt) was investigated further for its dissolution ability.
See the full brochure Itraconazole Amorphous Solid Dispersions Tablet here:
(click the picture to download the brochure)
Source: MEDELPHARM brochure Itraconazole Amorphous Solid Dispersions Tablet