Supporting Dose Form Development

Summary

Agenda1 have a long history of involvement in novel  dose form development and have  extensive knowledge and experience in this area, consequently they regularly  combine a range of techniques to support their clients’ goals.  This example included particle sizing, blending and content uniformity testing, in addition it involved the establishment of  API micronization equipment inside a glove box to facilitate low humidity milling.

Background

Early stage dose form development is an important task during drug product development as it precedes pre clinical efficacy and safety testing. Selection of an appropriate dose form is often a trade off between the route of action, dose form preference and practicality.

Dosage form design depends greatly on the physical properties of the active and compatible excipient components with the properties being closely linked to the final product specification such as uniformity, stability and mechanical durability. The majority of early stage formulation development work supported by Agenda1 is to understand the how the solubility of the product is impacted by changes to the physical form (size, surface area, porosity, amorphous nature, polymorph etc).

Resources

Agenda1 have a wide range of in house equipment that is maintained to pharmaceutical Good Manufacturing Practise (cGMP) standards  operated by  its team of  experienced scientists.

In this example, the original sample (a pulmonary product) was processed  using a micronizer to mill to a respirable size before being blended with a lactose carrier (all work carried out by Agenda 1).

Equipment used to carry out the work above included (both pre and post micronization);

DSC – Confirmed the physical structure of the material pre and post  milling as the material could take in or lose moisture which could have impacted the form.

TGA – to determin non-specific solvent levels of the starting material before milling, and also ascertain the melting point to understand if there were specific risks when milling.

BET SSA – Determined the surface area of the particles after milling which helped determine the impact this factor might have on dissolution, and was indicative of the homogeneity of the sample after milling.

XRD – X-Ray Diffraction produced a diffraction pattern for a sample which was then compared to a starting material, to ensure that high levels of amorphicity had not been introduced during milling.

SEM – Allowed the exact structure of the material to be viewed by the client.

Particle Sizing – A key factor to ensure the particle were of respirable size

HPLC – after blending with lactose formulation was assessed for content uniformity at levels ranging between 5% w/w to 0.1% w/w.

Activities

In this example, the client supplied the Active Pharmaceutical Ingredient and requested that Agenda1 carry out low humidity milling which was  carried out in a  low humidity glove box.

Prior to milling, the starting material was fully characterized by Size, Surface Area, XRD, DSC and TGA. In addition an HPLC method was transferred into the laboratory.

The milled material was then measured for particle size, to ensure respirable particles had been manufactured. Whilst that work was proceeding, an HPLC method was adopted. After milling and checking that the material had remained crystalline, the API was blended at various concentration levels with a carrier material (lactose). This work was supported by Agenda1’s long history of involvement in pulmonary dose form development and understanding of the challenges in this area.

Results

The subsequent blends were tested for content uniformity by HPLC before being released and supported by a certificate of analysis.  This completion of this work was to a tightly defined, agreed timeline, as the material produced here was then passed to another laboratory for further work.